3-amidoindolyl derivatives

ABSTRACT

The present invention is directed to a new class of 3-amido and 3-sulfamido-indolyl NMDA antagonists and their use in the treatment of a number of disease states.

RELATED APPLICATION

This is a division of application Ser. No. 08/372,710, filed Jan. 13,1995; U.S. Pat. No. 5,491,153 which is a continuation of applicationSer. No. 08/197,101, filed Feb. 15, 1994, now abandoned; which is acontinuation of application Ser. No. 07/977,974, filed Nov. 18, 1992,now abandoned; which is a division of application Ser. No. 07/795,572,filed Nov. 21, 1991, now issued U.S. Pat. No. 5,189,054, issued Feb.23,1993; which is a continuation in part of application Ser. No.07/608,457, filed Nov. 2, 1990, now abandoned, which is hereinincorporated by reference.

The present invention is directed to a new class of 3-amido and3-sulfamido-indolyl derivatives that are useful as NMDA antagonists.Another aspect of the invention is directed to their use in thetreatment of a number of diseases as well as to pharmaceuticalcompositions containing them.

In accordance with the present invention, a new class of NMDAantagonists have been discovered which can be described by the followingformulae: ##STR1## in which Z is represented by H, C₁ -C₄ alkyl, phenyl,substituted phenyl, or an alkylphenyl substituent in which the phenylring may be optionally substituted; R is represented by hydrogen,halogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, CF₃, OCF₃, OH, NO₂, or CN; B isrepresented by hydrogen, C₁ -C₄ alkyl, optionally substitutedalkylphenyl, or --CH₂ --COR₂ ; X is represented by CO or SO₂ ; A isrepresented by a substituent selected from the group consisting of:##STR2## in which L is represented by a substituent selected from thegroup consisting of hydrogen, halogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, CF₃,OCF₃, OH, NO₂, NH₂, alkylphenyl, acetyloxy, or CN; R₁, R₂, and D areeach independently represented by a substituent selected from the groupconsisting of --OH, --OR₃, --NR₄ R₅, --OCH₂ OR₃, and --O--(CH₂)_(m)--NR₆ R₇, in which m is an integer from 1-4; R₃ is represented by C₁ -C₄alkyl, phenyl, substituted phenyl or an alkylphenyl substituent in whichthe phenyl ring may be optionally substituted; R₄ and R₅ are eachindependently represented by hydrogen or a C₁ -C₄ alkyl; R₆ and R₇ areeach independently represented by hydrogen or a C₁ -C₄ alkyl, or R₆ andR₇ together with the adjacent nitrogen atom form a piperidino,morpholino, or pyrrolidino group; the pharmaceuticaly acceptable saltthereof; with the following proviso's 1) that when R, Z, B, arehydrogen, R₁ is OR₃ in which R₃ is ethyl, and X is CO, then L is nothydrogen; 2) that when X is SO₂, R and B are hydrogen, and Z is methyl,then L is not para NO₂ or para Methyl; 3) that when X is SO₂, R and Bare hydrogen, and Z is H, then L is not para C_(1;) 4) that when X isSO₂, A cannot be C(O)--D or tetrazole.

As used in this application:

a) the term "halogen" refers to a fluorine, chlorine, or bromine atom;

b) the terms "lower alkyl group and C₁₋₄ alkyl" refer to a branched orstraight chained alkyl group containing from 1-4 carbon atoms, such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc.;

c) the terms "lower alkoxy group and C₁₋₄ alkoxy" refer to a straight orbranched alkoxy group containing from 1-4 carbon atoms, such as methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, etc.;

d) the term "substituted phenyl ring" refers to a phenyl moiety (C₆ H₅)which is substituted with up to 3 substituents, each substituent isindependently selected from the group consisting of halogens, C₁₋₄alkyl, C₁₋₄ alkoxy, CF₃, OCF₃, OH, CN, NH₂ and NO₂. These substituentsmay be the same or different and may be located at any of the ortho,meta, or para positions.

e) the term "alkylphenyl substituent" refers to the following structure,--(CH₂)_(p) --C₆ H₅, in which p is an integer from 1-3. This phenyl ringmay be substituted in the manner described immediately above unlesssubstitution is expressly excluded.

f) the term "unsubstituted alkylphenyl substituent" refers to thefollowing structure, --(CH₂)_(p) --C₆ H₅, in which p is an integer from1-3.

f) the expression pharmaceutically acceptable additions salts thereofrefers to either acid addition salts or to basic additions salts;

g) the term carbonyl refers to: CO,

h) the term sulfoxide refers to: SO₂, and;

i) the term tetrazole refers to: ##STR3##

The expression "pharmaceutically acceptable basic addition salts" isintended to apply to any non-toxic organic or inorganic basic additionsalts of the compounds represented by Formula I or any of itsintermediates. Illustrative bases which form suitable salts includealkali metal or alkaline-earth metal hydroxides such as sodium,potassium, calcium, magnesium, or barium hydroxides; ammonia, andaliphatic, alicyclic, or aromatic organic amines such as methylamine,dimethylamine, trimethylamine, and picoline. Either the mono- ordi-basic salts can be formed with those compounds.

The expression "pharmaceutically acceptable acid addition salts" isintended to apply to any non-toxic organic or inorganic acid additionsalt of the base compounds represented by Formula I or any of itsintermediates. Illustrative inorganic acids which form suitable saltsinclude hydrochloric, hydrobromic, sulphuric, and phosphoric acid andacid metal salts such as sodium monohydrogen orthophosphate, andpotassium hydrogen sulfate. Illustrative organic acids which formsuitable salts include the mono-, di-, and tricarboxylic acids.Illustrative of such acids are for example, acetic, glycolic, lactic,pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric,ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic,cinnamic, salicyclic, 2-phenoxy-benzoic, p-toluenesulfonic acid, andsulfonic acids such as methane sulfonic acid and 2-hydroxyethanesulfonic acid. Such salts can exist in either a hydrated orsubstantially anhydrous form.

The indole ring depicted in Formulae Ia-c is always substituted atpositions 2 and 3, and may be optionally substituted at position 1. Itmay be further substituted as is indicated by the possible definitionsfor R. R may represent up to 3 additional substituents and theseadditional substituents may be located at any of positions 4, 5, 6, or7. These substituents can be the same or different. X may be representedby either C(O) or SO₂. If X is SO₂, then A should not be C(O)--D ortetrazole.

R₁ R₂, and D may contain either a phenyl or an alkylphenyl substituentin which the phenyl ring may be optionally substituted. There may be upto 3 substituents occuring on these phenyl rings and these substituentsmay be located at any of the ortho, meta, or para positions. Thespecific substitutions may be any of those listed above in thedefinition of substituted phenyl ring. Z may also be represented eitherby a substituted phenyl ring or an alkyl phenyl substituent in which thephenyl ring may be substitued. These phenyl rings may also contain up to3 substitutents which may be located at any of the ortho, meta, or parapositions. The specific substitutions may be any of those listed abovein the definition of substituted phenyl ring.

R₁, R₂, and D may be represented by the same substituent or differingsubstitutents. Likewise R₄ and R₅ may be represented by the samesubstitutent or differing substitutents. When R₆ and R₇ are representedby hydrogen or a C₁₋₄ alkyl, they may represent the same or differingsubstituents. When R₆ and R₇ form a hetrocyclic ring along with theindicated nitrogen atom, the nitrogen atom of the hetrocycle is alwaysbonded to the adjacent alkylene group.

It is preferred for the indolyl ring to be substituted, more preferablyfor the substitution to occur at positions 4 and 6, 5 and 6, or 6. It isalso prefered that these substituents be halogen atoms such as chlorineatoms. It is preferred for B to be a non-hydrogen substituent and for Ato be phenyl.

Examples of compounds encompassed by the present invention include:

1) 3- (2-hydroxyphenacyl)amino!-2-carboxy-6-chloroindole;

2) 3- (phenacyl)amino!-2-carboxy-6-chloroindole;

3) 3- (phenacyl)amino!-2- (2-dimethylamino)carbethoxy!-6-chloroindole;

4) 3- (phenacyl)amino!-2-carbethoxy-6-chloroindole;

5) 3- (2-acetoxyphenacyl)amino!-2-carbethoxy-6-chloroindole;

6) 3- (oxalyl)amino!-2-carboxy-6-chloroindole;

7) 3- (methyloxalylate)amino!-2-carbmethoxy-6-chloroindole;

8) 3- (phenacyl)methylamino!-2-carboxy-4,6-dichloroindole;

9) 3- (phenacyl)amino!-2-carboxy-4,6-dichloroindole;

10) 3- (oxalyl)amino!-2-carboxy-4,6-dichloroindole;

11) 3- (3-pyridacyl)methylamino!-2-carboxy-4,6-dichloroindole;

12) 3- (3-pyridacyl)methylamino!-2-carbethoxy-4,6-dichloroindole;

13) 3- (3-pyridacyl)amino!-2-carbethoxy-4,6-dichloroindole;

14) 3- (3-pyridacyl)amino!-2-carboxy-4,6-dichloroindole;

15) 3- (phenacyl)methylamino!-2-(2-dimethylamino)carbethoxy!-4,6-dichloroindole;

16) 3- (phenacyl)methylamino!-2-carbethoxy-4,6-dichloroindole;

17) 3- (phenacyl)amino!-2-carbethoxy-4,6-dichloroindole;

18) 3- (methyloxalylate)amino!-2-carbethoxy-4,6-dichloroindole;

19) 3- (2-benzylphenacyl)amino!-2-carbethoxy-4,6-dichloroindole;

20) 3- (2-benzylphenacyl)amino!-2-carboxy-4,6-dichloroindole;

21) 3- (2-benzylphenacyl)methylamino!-2-carbethoxy-4,6-dichloroindole;

22) 3- (2-benzylphenacyl)methylamino!-2-carboxy-4,6-dichloroindole;

23) 3- (phenylsulfonyl)amino!-2-carbethoxy-4,6-dichloroindole;

24) 3- (phenylsulfonyl)amino!-2-carboxy-4,6-dichloroindole;

25) 3- (phenacyl)ethylamino!-2-carbethoxy-4,6-dichloroindole;

26) 3- (phenacyl)ethylamino!-2-carboxy-4,6-dichloroindole;

27) 3- (phenacyl)benzylamino!-2-carbethoxy-4,6-dichloroindole;

28) 3-(phenacyl)carbethoxymethyl-amino!-2-carbethoxy-4,6-dichloroindole;

29) 3- (phenacyl)benzylamino!-2-carboxy-4,6-dichloroindole;

30) 3- (phenacyl)carboxymethyl-amino!-2-carboxy-4,6-dichloroindole;

31) 3- (phenylsulfonyl)methylamino!-2-carbethoxy-4,6-dichloroindole;

32) 3- (phenylsulfonyl)methylamino!-2-carboxy-4,6-dichloroindole;

33) 3- (4-nitrophenacyl)amino!-2-carbethoxy-4,6-dichloroindole;

34) 3- (4-aminophenacyl)amino!-2-carbethoxy-4,6-dichloroindole;

35) 3- (methyloxalylate)benzylamino!-2-carbethoxy-4,6-dichloroindole;

36) 3- (methyloxalylate)methylamino!-2-carbethoxy-4,6-dichloroindole;

37) 3- (4-nitrophenacyl)amino!-2-carboxy-4,6-dichloroindole;

38) 3- (oxalyl)benzylamino!-2-carboxy-4,6-dichloroindole;

39) 3- (oxalyl)methylamino!-2-carboxy-4,6-dichloroindole.

A general synthetic procedure for the preparation of compounds ofFormula Ia is set forth in Scheme Ia. In Scheme I, all substituents,unless otherwise indicated, are as previously defined. ##STR4## R'₁ =OR₃B'=C₁ -C₄ alkyl, --CH₂ --COR₂, or alkylphenyl

Z'=C₁ -C₄ alkyl or alkylphenyl, phenyl or substitued phenyl

Hal=Cl or Br

In general, an appropriate 3-amidoindolyl derivative of Formula Ia canbe prepared in a multi-step process.

In Scheme I, the 2-aminobenzonitrile derivative as described bystructure (1) is obtained commercially or prepared from theappropriately substituted 2-nitrobenzoic acid by one of ordinary skillin the art. For example, the appropriate 2-nitrobenzoic acid derivativecan be converted to the acid chloride with a chlorinating reagent suchas thionyl chloride and then coupled with tert-butylamine to provide theappropriately substituted amide. The nitro functionality is then reducedby reacting the derivative dissolved in a protic solvent such as ethanolwith hydrogen in the presence of a catalyst such as palladium on carbon.The resulting aniline deriviative is then dehydrated by treatment withtrifluoroacetic anhydride in an organic solvent such as methylenechloride at room temperature to afford the appropriately substituted2-aminobenzonitrile of structure (1) as the N-trifluoroacetate which isused directly in step a of Scheme I.

The appropriately substituted 2-aminobenzonitrile as described bystructure (1) in Scheme I can be prepared using another method by one ofordinary skill in the art. For example, the appropriate 2-aminobenzoicacid derivative can be converted to the succinimide ester by treatmentwith triphenylphosphine, diethyl azodicarboxylate and N-hydroxysuccinimide in an organic solvent such as tetrahydrofuran to provide thesuccinimide ester. This is then treated with tert-butylamine at roomtemperature in an organic solvent such as tetrahydrofuran to provide theN-tert-butylamide derivative. This compound is dehydrated withtrifluoroacetic anhydride in an organic solvent such as methylenechloride at room temperture to afford the appropriately substituted2-aminobenzonitrile of structure (1) as the N-trifluoroacetate which isused dirctly in step a of Scheme I.

Step a of Reaction Scheme I, a 2-aminobenzonitrile derivative asdescribed by structure (1) is subjected to an alkylation reaction withan alkyl haloacetate derivative as described by structure (2) to producean alkyl 2-anilinoacetate derivative as described by structure (3).

The alkylation reaction of Step a can be carried out using techniquesknown in the art. Typically, the 2-aminobenzonitrile derivativedescribed by structure (1) is contacted with a molar excess of an alkylhaloacetate derivative as described by structure (2) and a molar excessof a base, such as potassium carbonate. The reactants are typicallycontacted in an organic solvent such as dimethylformamide. The reactantsare typically stirred together for a period of time from about 24 hoursto 6 days at a temperature range of from room temperature to reflux. Theanilinoacetate derivative as described by structure (3) can be recoveredfrom the reaction by techniques such as flash chromatography. It canthen be optionally purified by recrystallization from a solvent such ashexane.

In Step b of Reaction Scheme I, an alkyl 2-anilinoacetate derivative asdescribed by structure (3) is cyclized with an appropriatenon-nucleophilic base, such as potassium tert-butoxide, to produce a2-carbalkoxy-3-amino indole as described by structure (4).

The cyclization reaction of Step b can also be carried out usingtechniques known in the art. Typically, the alkyl 2-anilinoacetatederivative as described by structure (3) is contacted with an equimolaramount of a base, such as potassium tert-butoxide. The reactants aretypically contacted in an anhydrous organic solvent such astetrahydrofuran. The reactants are typically stirred together for aperiod of time from about 3 hours to 24 hours at a temperature range ofabout 0° C. to room temperature. The 2-carbalkoxy-3-amino indole asdescribed by structure (4) can be recovered from the reaction bytechniques such as flash chromatography. It can then be optionallypurified by recrystallization from a solvent system such as hexane/ethylacetate.

In Step c of Reaction Scheme I, the amino functionality of a2-carbalkoxy-3-amino indole as described by structure (4) is subjectedto an acylation reaction with an appropriate acid chloride or sulfonylchloride as described by structure (5) to produce a 3-amidoindolylderivative as described by structure (6).

The acylation reaction of step c can also be carried out usingtechniques known in the art. Typically, the 2-carbalkoxy-3-amino indoleas described by structure (4) is contacted with a molar excess of anacid chloride or sulfonyl chloride and a molar excess of a base, such astriethylamine. The reactants are typically contacted in an anhydrousorganic solvent, such as tetrahydrofuran or methylene chloride. Thereactants are typically stirred together for a period of time rangingfrom 5 minutes to 24 hours and at a temperature range of from roomtemperature to reflux. The 3-amidoindolyl derivative as described bystructure (6) can be recovered from the reaction by techniques such asrecrystallization from a solvent system such as hexane/ethyl acetate.

In addition, the 3-amidoindolyl derivative as described by structure (6)can be further fuctionalized as described by Optional Steps d-g inReaction Scheme I.

For example, in Optional Step d₁, the indole nitrogen functionality ofthe 3-amidoindolyl derivative as described by structure (6) can besubjected to an alkylation reaction to produce a 3-amido-1-alkylindolylderivative as described by structure (7).

One method for carrying out the alkylation reaction of optional step d₁can be carried out using techniques known in the art. Typically, the3-amidoindolyl derivative as described by structure (6) is firstcontacted with a molar excess of a base, such as sodium hydride. Thereactants are typically contacted in an anhydrous organic solvent, suchas tetrahydrofuran or dimethylformamide. The reactants are typicallystirred together for a period of time ranging from 15 minutes to 5 hoursand at a temperature range of from 0° C. to room temperature.

A molar excess of an alkyl halide derivative as described by structure(9a) is then added and the reactants are stirred together for a periodof time ranging from 2 hours to 24 hours and at a temperature range offrom -10° C. to room temperature. The 3-amido-1-alkylindolyl derivativeas described by structure (7) is recovered from the reaction bytechniques such as flash chromatography. It can then be optionallypurified by recrystallization from a solvent system such as ethylacetate/hexane.

Another suitable alkylation method is to contact a compound as describedby structure (6) with a molar excess of triphenylphosphene, a molarexcess of diethylazodicarboxylate, and an appropriate alcohol derivativeas described by structure (9b). The reactants are typically contacted inan anhydrous organic solvent, such as tetrahydrofuran. The reactants aretypically stirred together for a period of time ranging from 1 hour to24 hours and at a temperature range of from 0° C. to room temperature.The 3-amido-1-alkylindolyl derivative as described by structure (7) isrecovered from the reaction by techniques such as flash chromatography.It can then be optionally purified by recrystallization from a solventsystem such as ethyl acetate/hexane.

In Optional Step d₂, the indole nitrogen functionality of the3-amidoindolyl derivative as described by structure (6) can be protectedby a suitable protecting group, such as tert-butyloxycarbonyl, to allowfurther functionalization.

The protection step of optional step d₂ can also be carried out usingtechniques known in the art. Typically, the 3-amidoindolyl derivative asdescribed by structure (6) is contacted with an equimolar amount ofdi-tert-butyl dicarbonate and a catalytic amount of a base, such asdimethylaminopyridine. The reactants are typically contacted in anorganic solvent, such as tetrahydrofuran. The reactants are typicallystirred together for a period of time ranging from 1 hour to 24 hours ata temperature range of from room temperature to reflux. The protected3-aminoindolyl derivative as described by structure (8) can be recoveredfrom the reaction by techniques such as flash chromatography. It canthen by optionally purified by recrystallization from a solvent systemsuch as ethyl acetate/hexane.

In Optional Step e, the 3-amido functionality of the suitably protected3-amidoindolyl derivative as described by structure (7) can be subjectedto an alkylation reaction to produce a 3-amidoindolyl derivative asdescribed by structure (11). Reactants and reaction conditions aretypically as described previously in optional step d₁.

In Optional Step f, the indole nitrogen protecting group functionalityof the 3-amidoindolyl derivative as described by structure (11) can beremoved under acidic conditions to produce a 3-N-alkylamidoindolylderivative as described by structure (12).

The deprotection reaction of optional step f can also be carried outusing techniques well known in the art. Typically, the protected3-amidoindolyl derivative described by structure (11) is contacted witha molar excess of an acid, such as trifluoroacetic acid. The reactantsare typically contacted in an organic solvent, such as methylenechloride. The reactants are typically stirred together for a period oftime ranging from 1 hour to 24 hours at a temperature range of 0° C. toreflux. The 3-N-alkylamidoindolyl derivative as described by structure(12) can be recovered from the reaction by techniques such as flashchromatography. It can then be optionally purified by recrystallizationfrom a solvent system such as ethyl acetate/hexane.

In Optional Step g, the indole nitrogen functionality of the3-N-alkylamidoindolyl derivative as described by structure (12) can besubjected to an alkylation reaction to produce a 3-amidoindolylderivative as described by structure (13). Typically, the reactants andreaction procedures are as described previously in optional step d₁.

In addition, those 3-amidoindolyl compounds of structures (6), (7),(12), and (13) in which either R₁ and/or R₂ are represented by --OC₁-C₄, can be further functionalized by either a deprotection reactionand/or an additional functionalization reaction.

The deprotection reaction can be carried out using hydrolytic techniquesknown per se. Typically, the protected 3-amidoindolyl derivative asdescribed by structures (6), (7), (12), or (13), in which either R₁and/or R₂ are represented by --OC₁ -C₄, is subjected to a basichydrolysis. The compound is contacted with a 2 to 3 molar excess of aninorganic base such as lithium hydroxide. The hydrolysis is carried outat a temperature range of from about 25° C. to about 50° C. for a periodof time ranging from 1 to 5 hours. The desired compound of Formula Iacan then be recovered from the reaction zone by flash chromatography andoptionally purified by recrystallization from a solvent system such asethyl acetate/hexane.

The various ester and amide derivatives encompassed by Formula Ia can beprepared by techniques known in the art. One method of preparing theamide derivatives is to contact a compound of Formula Ia, in whicheither R₁ and/or R₂ is represented by --OH, with a halogenating agentsuch as thionyl chloride, oxalyl chloride, phosphorus oxychloride,phosphorus pentachloride, etc. The resulting mono or diacid halides isthen contacted with an excess of an amine represented by --HNR₃ R₄, inwhich R₃ and R₄ are as previously defined. In a similar fashion, theester derivatives can be prepared by contacting the mono or diacidhalides with an excess of an alcohol represented by HOC₁ -C₄.

Another suitable esterification method is to contact a compound ofFormula Ia, in which either R₁ and/or R₂ are represented by OH, with abase, such as diethylisopropylamine, in a polar inert solvent, such asdimethylformamide, dimethylsulfoxide, acetonitrile, acetone ortetrahydrofuran, thereby forming a mono or his carboxylate salt. Themono or bis carboxylate salt is then contacted with 2 to 5 equivalents,preferable about 2.5 equivalents, of an alkylhalide corresponding to thedesired ester, and allowed to react at a temperature of about 25° C. fora period of time ranging from 16-24 hours. The reaction mixture is thenquenched with dilute aqueous acid and extractive work-up known in theart affords the mono or diester compounds of Formula Ia, which can bepurified by standard methods such as chromatography orrecrystallization.

Another suitable esterification method is to contact a compound ofFormula Ia, in which either R₁ and/or R₂ are represented by OH, with analcohol of the formula HOC₁ -C₄ in the presence of an acid such assulfuric acid. The esterification is typically conducted at elevatedtemperatures. The desired compound of Formula Ia can then be recoveredfrom the reaction zone by flash chromatography and optionally purifiedby recrystallization from a solvent system such as ethyl acetate/hexane.

Another suitable esterification method is to contact a compound ofFormula Ia, in which either R₁ and/or R₂ are represented by OH, with amolar excess of an alcohol of the formula HOC₁ -C₄, a molar excess oftriphenylphoshine, and a molar excess of diethylazodicarboxylate. Thereactants are typically contacted in an anhydrous organic solvent, suchas tetrahydrofuran. The reactants are typically stirred together for aperiod of time ranging from 1 hour to 24 hours and at a temperaturerange of from 0° C. to room temperature. The ester derivative isrecovered from the reaction by techniques such as flash chromatography.It can then be optionally purified by recrystallization from a solventsystem such as ethyl acetate/hexane.

Amides can also be prepared by contacted esters of Formula Ia, in whicheither R₁ and/or R₂ are represented by --OC₁ C₄ with an amine of theformula HNR₃ R₄ at a temperature of from 0°-100° C. for a period of timeranging from 1-48 hours in an intert solvent such as tetrahydrofuran.The resulting amide derivative of Formula Ia can then be isolated andpurified by techniques known in the art.

The starting materials for use in the general synthetic procedureoutlined in Scheme I are readily available to one of ordinary skill inthe art.

A general synthetic procedure for the preparation of compounds ofFormula Ib is set forth in Scheme II. In Scheme II, all substituents,unless otherwise indicated, are as previously defined. ##STR5##

In general, an appropriate 3-amidoindolyl derivative of Formula Ib canbe prepared in a multi-step synthesis.

In Scheme II step a, the 2-carboxyindolyl derivative (14) prepared asdescribed previously in Scheme I, is treated with a chlorinating agentsuch as thionyl chloride in an organic solvent such as toluene withheat, followed by treatment with tert-butylamine to yield theappropriately substituted 2-carboxamidoindole of structure (15).

In Scheme II step b, the 2-carboxamidoindolyl derivative of structure(15) can then be dehydrated by treatment with trifluoroacetic anhydridein an organic solvent such as methylene chloride at room temperture toprovide the 2-cyanoindolyl derivative of structure (16).

In Scheme II step c, the 2-cyanoindoyl derivative of structure (16) canthen be treated with tributyltin chloride and sodium azide in an organicsolvent such as N-methylpyrrolidinone at 70° C. for approximately 70hours (Carini, D. J. et al. J. Med. Chem. (1991), 34, 1834). Aftercooling, a workup and purification familiar to one skilled in the artwill yield the appropriately substituted 2-tetrazoleindole as describedby Formula Ib.

A general synthetic procedure for the preparation of compounds ofFormula Ia where A and/or R1 can be a tetrazole substituent is set forthin Scheme III. In Scheme III, all substituents, unless otherwiseindicated, are as previously defined. ##STR6##

In general, an appropriate 3-amidoindolyl derivative of Formula Ia,where A and/or R₁ are tetrazole substituents, can be prepared in amulti-step process.

In Scheme III step a, the appropriately substituted 3-aminoindole ofstructure (17) can be treated with an equivalent of methyl oxalylchloride, in the presence of an organic amine acid scavenger, in anorganic solvent such as tetrahydrofuran at room temperture to providethe 3-amidoindolyl derivative of structure (18).

The 3-aminoindolyl derivative of structure (18) can optionally beN-alkylated in Scheme III step b, following the procedure previously setforth in Scheme I to provide the 3-aminoindolyl derivative of structure(19).

The 3-aminoindolyl derivative of structure (19) can again be optionallyN-alkylated in Scheme III step c, following the procedure previously setforth in Scheme I to provide the 3-aminoindolyl derivative of structure(20).

The appropriately substituted 3-aminoindole of structure (20) can thenbe selectively deprotected by treatment with one equivalent of base suchas lithium hydroxide in a solvent mixture such as tetrahydrofuran/waterat room temperature to provide the monoacid of structure (21).

The monoacid of structure (21) can then be converted to the amidederivative of structure (22) by treatment with triphenylphosphine,diethyl azodicarboxylate and N-hydroxysuccinimide in an organic solventsuch as tetrahydrofuran to provide the succinimide ester. This is thentreated with tert-butylamine at room temperature in an organic solventsuch as tetrahydrofuran to provide the amide derivative of structure(22). This can then be converted to the tetrazole derivative ofstructure (24) by following steps f and g which have been previouslydescribed in Scheme II, steps b and c. Compound (24) can then bedeprotected by treatment with trifluoroacetic acid in an organic solventsuch as methylene chloride at room temperature to provide the tetrazolederivative of structure (25).

Steps e, f and g of Scheme III can then be repeated on the2-carboxyindolyl derivative of structure (25) to provide theappropriately substituted ditetrazole derivative of structure (26).

A general synthetic procedure for the preparation of compounds ofFormula Ic is set forth in Scheme IV. In Scheme IV, all substituentsunless otherwise indicated are as previously defined. ##STR7##

In general, an appropriate 3-amidoindolyl derivative of Formula Ic canbe prepared as described by Scheme IV. The appropriately substituted3-amidoindolyl of structure (14) can be treated with an excess of achlorinating reagent such as thionyl chloride in an organic solvent suchas toluene at a temperature of 23°-80° C. for 1 hour to 6 hours. Theresulting acid chloride of structure (14) is then treated with a molarequivalent of 5-aminotetrazole in an organic solvent such as methylenechloride at room temperature for 1 hour to 1 day to provide the3-amidoindolyl derivative of structure (27).

The starting materials for use in the general synthetic proceduresoutlined in Schemes II, III and IV are available to one skilled in theart.

The following examples present typical syntheses as described by SchemeI through Scheme IV. These examples are understood to be illustrativeonly and are not intended to limit the scope of the invention in anyway. As used in the following examples, the following terms have themeanings indicated: "g" refers to grams, "mmol" refers to millimoles,"mL" refers to milliliters, "°C." refers to degrees Celsius, "TLC"refers to thin layer chromatography, "mg" refers to milligrams, "μL"refers to microliters, "eq" refers to equivalents.

EXAMPLE 1

Preparation of 3- (2-Acetoxyphenacyl)amino!-2-carbmethoxy-6-chloroindole##STR8## Step a: 2-(Carbmethoxy)methylamino-4-chlorobenzonitrile

Dissolve 2-amino-4-chlorobenzonitrile (12.9 g, 85 mmol) in anhydrousdimethylformamide (15 mL). Add potassium carbonate (7.6 g, 90 mmol) andmethyl bromoacetate (7.8 mL, 90 mmol) and stir at 70° C. for 5 days. Addadditional methyl bromoacetate (78 mL, 90 mmol) and continue heating for1 day. Dilute with ethyl acetate (300 mL), wash with water, separate theorganic phase and dry (MgSO₄). Evaporate the solvent in vacuo and purifyby flash chromatography (25% ethyl acetate/hexane). Recrystallize(hexane) to give the title compound (7 g, 36%).

Step b: 3-Amino-2-carbmethoxy-6-chloroindole

Dissolve potassium tert-butoxide (44 mmol) in anhydrous tetrahydrofuran(80 mL) and cool to 5° C. Add a solution of2-(carmethoxy)methylamino-4-chlorobenzonitrile (10 g, 44 mmol) inanhydrous tetrhydrofuran (80 mL). Allow to warm to room temperature andstir for 3 hours. Pour into water/ethyl acetate, separate the organicphase and dry (MgSO₄). Evaporate the solvent in vacuo and purify byflash chromatography (25% ethyl acetate/hexane followed by 50% ethylacetate/hexane) and recrystallize (ethyl acetate/hexane) to give thetitle compound; first crop (5.5 g, 55%) and second crop (1.9 g, 19%).

Step c: 3- (2-Acetoxyphenacyl)amino!-2-carboxy-6-chloroindole

Dissolve 3-amino-2-carbmethoxy-6-chloroindole (1 g, 4.4 mmol) inanhydrous tetrahydrofuran (50 mL). Add triethylamine (4.8 mmol) andacetylsalicoyl chloride (4.8 mmol) and stir for 5 minutes. Dilute intoethyl acetate (500 mL), separate the organic phase, wash with water,saturated sodium hydrogen carbonate and saturated sodium chloride. Dryand evaporate the solvent in vacuo. Recrystallize to give the titlecompound (1.3 g, 79%); mp 184°-86° C.

Anal. Calcd for C₁₉ H₁₅ ClN₂ O₅ : C, 59.00; H, 3.91; N, 7.24; Found: C,58.90; H, 3.88; N, 7.11.

EXAMPLE 2

Preparation of 3- (2-Hydroxyphenacyl)amino!-2-carboxy-6-chloroindole##STR9##

Dissolve 3- (2-acetoxyphenacyl)amino!-2-carbmethoxy-6-chloroindole (800mg, 2.15 mmol) in tetrahydrofuran/water (20 mL, 1/1). Add lithiumhydroxide monohydrate (932 mg, 8.5 mmol). Seal the flask and warm to 60°C. for 3 hours. Dilute with ethyl acetate/water, acidify and separatethe organic phase. Dry, precipitate with hexane and filter the solid togive the title compound (358 mg, 50%); mp 198°-200° C. (dec).

EXAMPLE 3

Preparation of 3- (Phenacyl)amino!-2-carbmethoxy-6-chloroindole##STR10##

Dissolve 3-amino-2-carbmethoxy-6-chloroindole (500 mg, 2.22 mmol) inmethylene chloride (10 mL). Add triethylamine (334 μL, 2.4 mmol) andbenzoyl chloride (2.4 mmol) and stir for 1 hour. Dilute into ethylacetate (300 mL), wash with water and saturated sodium chloride. Dry andevaporate the solvent in vacuo. Recrystallize to give the titlecompound; first crop (570 mg, 78%) and second crop (70 mg, 9%); mp242°-43° C.

EXAMPLE 4

Preparation of 3- (Phenacyl)amino!-2-carboxy-6-chloroindole ##STR11##

Dissolve 3- (phenacyl)amino!-2-carbmethoxy-6-chloroindole (480 mg, 1.46mmol) in tetrahydrofuran/water (20 mL, 1/1). Add lithium hydroxidemonohydrate (316 mg, 2.92 mmol). Seal the flask and warm to 60° C. for 3hours. Dilute with ethyl acetate/water (50 mL/50 mL) and separate theorganic phase. Acidify the aqueous phase and extract with ethyl acetate.Dry (MgSO₄) the combined organic phases and concentrate in vacuo.Precipitate with hexane to give the title compound; first crop (289 mg,63%) and second crop (74 mg, 16%); mp 205°-210° C. (dec).

EXAMPLE 4a

Preparation of 3- (phenacyl)methylamino!-2-carbmethoxy-6-chloroindole##STR12## Scheme I, step d₂ : 3-(phenacyl)amino!-2-carbmethoxy-6-chloro-1-(tert-butyloxycarbonyl)-indole

Mix 3- (phenacyl)amino!-2-carbmethoxy-6-chloroindole (130 mg, 0.395mmol), di-tert-butyl dicarbonate (89 mg, 0.395 mmol), tetrahydrofuran (5mL), dimethylaminopyridine (4 mg) and stir at room temperture overnight.Dilute the reaction with ethyl acetate (25 mL), wash with water, dryover magnesium sulfate, filter and concentrate in vacuo. Recrystallizethe residue from ethyl acetate/hexane to yield the title compound as awhite fluffy solid (160 mg, 95%).

Scheme I, step e: 3-(phenacyl)methylamino!-2-carbmethoxy-6-chloro-1-(tert-butyloxycarbonyl)-indole

Suspend sodium hydride (14.4 mg of a 60% dispersion, 0.36 mmol) inanhydrous tetrahydrofuran (1 mL) and cool to 0° C. under a nitrogenatmosphere. Add 3-(phenacyl)amino!-2-carbmethoxy-6-chloro-1-(tert-butyloxycarbonyl)-indole(140 mg, 0.326 mmol) in tetrahydrofuran/dimethylformamide (2 mL, 3:1)dropwise to the suspension. Stir at 0° C. for 30 minutes. Add methyliodide (0.0224 mL, 0.36 mmol) and stir for 30 minutes at 0° C. Warm thereaction to room temperature and quench with water and extract withethyl acetate. Rinse the organic phase with saturated sodium chloride,dry over magnesium sulfate, filter and concentrate in vacuo to yield thetitle compound (130 mg).

Scheme I, step f: 3- (phenacyl)methylamino!-2-carbmethoxy-6-chloroindole

Dissolve 3-(phenacyl)methylamino!-2-carbmethoxy-6-chloro-1-(tert-butyloxycarbonyl)-indolefrom above in methylene chloride (3 mL). Add trifluoracetic acid (1 mL)and stir for 2 hours. Dilute into ethyl acetate and rinse with saturatedsodium bicarbonate. Dry the organic phase over magnesium sulfate, filterand concentrate in vacuo to yield the title compound.

EXAMPLE 4b

Preparation of 3- (phenacyl)methylamino!-2-carboxy-6-chloroindole##STR13##

Dissolve 3- (phenacyl)methylamino!-2-carbmethoxy-6-chloroindole fromabove, in tetrahydrofuran (5 mL) and water (5 mL). Add lithium hydroxideand stir for 8 hours at 40° C. Dilute the reaction with water(10 mL) andethyl acetate (10 mL). Separate the layers and acidify the aqueouslayer. Extract the aqueous with ethyl acetate, dry the organic phaseover magnesium sulfate, filter and concentrate in vacuo. Recrystallizefrom ethyl acetate/hexane to yield the title compound (75 mg); mp250°-255° C.

Anal. Calcd for C₁₇ H₁₃ ClN₂ O₃ : C, 62.11; H, 3.99; N, 8.52; Found: C,61.77; H, 4.20; N, 8.62.

EXAMPLE 4c

Preparation of 3- (m-fluorophenacyl)amino!-2-carbmethoxy-6-chloroindole##STR14##

Suspend the 3-amino-2-carbmethoxy-6-chloroindole (1 g, 4.45 mmol) inmethylene chloride (50 mL) and add triethylamine (0.416 mL, 4.6 mmol) toproduce a mostly clear solution. Add the m-fluorobenzoyl chloride (0.561mL, 4.6 mmol) and stir for five minutes at room temperature to produce athick white precipitate. Dilute the reaction with ethyl acetate (700mL), rinse with water, dry over magnesium sulfate, filter andconcentrate in vacuo to 300 mL. Recrystallize by adding hot hexane (150mL) to the already hot solution of ethyl acetate to yield the titlecompound.

EXAMPLE 4d

Preparation of 3-(m-fluorophenacyl)methylamino!-2-carbmethoxy-6-chloroindole ##STR15##Scheme I, Step d₂ : 3-(m-fluorophenacyl)amino!-2-carbmethoxy-6-chloro-1-(tert-butyloxycarbonyl)-indole

Mix 3- (m-fluorophenacyl)amino!-2-carbmethoxy-6-chloroindole (1.5 g, 4.3mmol), di-tert-butyl dicarbonate (982 mg, 4.5 mmol), tetrahydrofuran (5mL), dimethylaminopyridine (42 mg, 0.4 mmol) and stir for severalminutes. Dilute the reaction with ethyl acetate, wash with water, dryover magnesium sulfate, filter and concentrate in vacuo to yield thetitle compound.

Scheme I, step e: 3-(m-fluorophenacyl)methylamino!-2-carbmethoxy-6-chloro-1-(tert-butyloxycarbonyl)-indole

Suspend sodium hydride (120 mg of a 60% dispersion, 3 mmol) in anhydroustetrahydrofuran (3 mL) and cool to 0° C. under a nitrogen atmosphere.Add 3-(phenacyl)amino!-2-carbmethoxy-6-chloro-1-(tert-butyloxycarbonyl)-indole(1.3 g, 2.9 mmol) in tetrahydrofuran/dimethylformamide (10 mL, 3:1)dropwise to the suspension producing a clear yellow solution at 15minutes. Stir at 0° C. for 30 minutes. Add methyl iodide (0.186 mL, 3mmol). Warm the reaction to room temperature and stir overnight. Quenchwith water (20 mL) and extract with ethyl acetate (20 mL). Rinse theorganic phase with saturated sodium chloride, dry and concentrate invacuo to yield the title compound.

Scheme I, step f: 3-(m-fluorophenacyl)methylamino!-2-carbmethoxy-6-chloroindole

Dissolve 3-(m-fluorophenacyl)methylamino!-2-carbmethoxy-6-chloro-1-(tert-butyloxycarbonyl)-indolefrom above in methylene chloride (5 mL). Add trifluoracetic acid (5 mL)and stir for 4 hours at room temperture. Dilute with ethyl acetate (50mL) and rinse with 1N sodium hydroxide, saturated sodium chloride, dryover magnesium sulfate, filter and concentrate in vacuo. Purify theresidue by flash chromatography (30% ethyl acetate/hexane) andrecrystallize from ethyl acetate/hexane to yield the title compound (700mg, 70%).

EXAMPLE 4e

Preparation of 3-(m-fluorophenacyl)methylamino!-2-carboxy-6-chloroindole ##STR16##

Dissolve 3- (m-fluorophenacyl)methylamino!-2-carbmethoxy-6-chloroindole(650 mg, 8 mmol) in tetrahydrofuran (10 mL) and water (10 mL). Addlithium hydroxide (227 mg, 5.4 mmol). Add methanol dropwise until anhomogeneous solution forms. Stir the reaction at room temperatureovernight. Dilute the reaction with water (10 mL) and ethyl acetate (25mL). Acidify with 1N HCl and separate the layers. Dry the organic phaseover magnesium sulfate, filter and concentrate 50% with heat.Reconstitute with hot hexane. Repeat the concentration andreconstitution steps and cool to yield the title compound (550 mg, 89%);mp 258°-260° C.

Anal. Calcd for C₁₇ H₁₂ ClFN₂ O₃ : C, 58.88; H, 3.49; N, 8.08; Found: C,58.63; H, 3.44; N, 7.78.

EXAMPLE 4f

Preparation of 3- (p-fluorophenacyl)amino!-2-carbmethoxy-6-chloroindole##STR17##

Suspend the 3-amino-2-carbmethoxy-6-chloroindole (1.15 g, 5.12 mmol) inmethylene chloride (80 mL) and add triethylamine (0.497 mL, 5.5 mmol).Add the p-fluorobenzoyl chloride (0.650 mL, 5.5 mmol) and stir for 30minutes at room temperature to produce a precipitate. Dilute thereaction with ethyl acetate (150 mL), rinse with water, dry overmagnesium sulfate, filter and concentrate in vacuo to yield the titlecompound.

EXAMPLE 4g

Preparation of 3-(p-fluorophenacyl)methylamino!-2-carbmethoxy-6-chloroindole ##STR18##Scheme I, step d₂ : 3-(p-fluorophenacyl)amino!-2-carbmethoxy-6-chloro-1-(tert-butyloxycarbonyl)-indole

Mix 3- (p-fluorophenacyl)amino!-2-carbmethoxy-6-chloroindole (1.7 g,5.12 mmol), di-tert-butyl dicarbonate (1.13 g, 5.12 mmol),tetrahydrofuran (50 mL), dimethylaminopyridine (52 mg, 0.5 mmol) andstir for 6 hours. Dilute the reaction with ethyl acetate, wash withwater, dry over magnesium sulfate, filter and concentrate in vacuo toyield the title compound.

Scheme I, step e: 3-(p-fluorophenacyl)methylamino!-2-carbmethoxy-6-chloro-1-(tert-butyloxycarbonyl)-indole

Suspend sodium hydride (240 mg of a 60% dispersion, 6 mmol) in anhydroustetrahydrofuran (3 mL) and cool to 0° C. under a nitrogen atmosphere.Add 3-(p-fluorophenacyl)amino!-2-carbmethoxy-6-chloro-1-(tert-butyloxycarbonyl)-indole(2.5 g, 5.6 mmol) in tetrahydrofuran/dimethylformamide (10 mL, 3:1)dropwise to the suspension producing a clear yellow solution at 15minutes. Stir at 0° C. for 30 minutes. Add methyl iodide (0.371 mL, 6mmol). Warm the reaction to room temperature and stir overnight. Quenchwith water (20 mL) and extract with ethyl acetate (20 mL). Rinse theorganic phase with saturated sodium chloride, dry and concentrate invacuo to yield the title compound.

Scheme I, step f: 3-(p-fluorophenacyl)methylamino!-2-carbmethoxy-6-chloroindole

Dissolve 3-(p-fluorophenacyl)methylamino!-2-carbmethoxy-6-chloro-1-(tert-butyloxycarbonyl)-indolefrom above in methylene chloride (5 mL). Add trifluoracetic acid (5 mL)and stir for 4 hours at room temperture. Dilute with ethyl acetate (50mL) and rinse with 1N sodium hydroxide, saturated sodium chloride, dryover magnesium sulfate, filter and concentrate in vacuo. Purify theresidue by flash chromatography (30% ethyl acetate/hexane) andrecrystallize from ethyl acetate/hexane to yield the title compound (1.0g, 62%).

EXAMPLE 4h

Preparation of 3-(p-fluorophenacyl)methylamino!-2-carboxy-6-chloroindole ##STR19##

Dissolve 3- (p-fluorophenacyl)methylamino!-2-carbmethoxy-6-chloroindole650 mg, 1.8 mmol) in tetrahydrofuran (10 mL) and water (10 mL). Addlithium hydroxide (227 mg, 5.4 mmol). Add methanol dropwise until anhomogeneous solution forms. Stir the reaction at room temperatureovernight. Dilute the reaction with water(10 mL) and ethyl acetate (25mL). Acidify with 1N HCl and separate the layers. Dry the organic phaseover magnesium sulfate, filter and concentrate 50% with heat.Reconstitute with hot hexane. Repeat the concentration andreconstitution steps and cool to yield the title compound (560 mg, 90%);mp 248°-250° C.

Anal. Calcd for C₁₇ H₁₂ ClFN₂ O₃ : C, 58.88; H, 3.49; N, 8.08; Found: C,58.75; H, 3.43; N, 7.70.

EXAMPLE 4i

Preparation of 3-(3,4-difluorophenacyl)amino!-2-carbmethoxy-6-chloroindole ##STR20##

Suspend the 3-amino-2-carbmethoxy-6-chloroindole (1.15 g, 5.2 mmol) inmethylene chloride (80 mL) and add triethylamine (0.497 mL, 5.5 mmol).Add the 3,4-difluorobenzoyl chloride (0.692 mL, 5.5 mmol) and stir for30 minutes at room temperature to produce a precipitate. Dilute thereaction with ethyl acetate, rinse with water, dry over magnesiumsulfate, filter and concentrate in vacuo to yield the title compound.

EXAMPLE 4j

Preparation of 3-(3,4-difluorophenacyl)methylamino!-2-carbmethoxy-6-chloroindole##STR21## Scheme I, step d₂ : 3-(3,4-difluorophenacyl)amino!-2-carbmethoxy-6-chloro-1-(tert-butyloxycarbonyl)-indole

Mix 3- (3,4-difluorophenacyl)amino!-2-carbmethoxy-6-chloroindole (5.2mmol), di-tert-butyl dicarbonate (1.19 g, 5.4 mmol), tetrahydrofuran (50mL), dimethylaminopyridine (52 mg, 0.5 mmol) and stir for 6 hours.Dilute the reaction with ethyl acetate, wash with water, dry overmagnesium sulfate, filter and concentrate in vacuo to yield the titlecompound.

Scheme I, step e:3-1(3,4-difluorophenacyl)methylamino!-2-carbmethoxy-6-chloro-1-(tert-butyloxycarbonyl)-indole

Suspend sodium hydride (188 mg of a 60% dispersion, 4.7 mmol) inanhydrous tetrahydrofuran (3 mL) and cool to 0° C. under a nitrogenatmosphere. Add 3-(phenacyl)amino!-2-carbmethoxy-6-chloro-1-(tert-butyloxycarbonyl)-indole(2 g, 4.3 mmol) in tetrahydrofuran/dimethylformamide (10 mL, 3:1)dropwise to the suspension producing a clear yellow solution at 15minutes. Stir at 0° C. for 30 minutes. Add methyl iodide (0.291 mL, 4.7mmol). Warm the reaction to room temperature and stir overnight. Quenchwith water (20 mL) and extract with ethyl acetate (20 mL). Rinse theorganic phase with saturated sodium chloride, dry and concentrate invacuo to yield the title compound.

Scheme I, step f: 3-(3,4-difluorophenacyl)methylamino!-2-carbmethoxy-6-chloroindole

Dissolve 3-(3,4-difluorophenacyl)methylamino!-2-carbmethoxy-6-chloro-1-(tert-butyloxycarbonyl)-indolefrom above in methylene chloride (5 mL). Add trifluoracetic acid (5 mL)and stir for 4 hours at room temperture. Dilute with ethyl acetate (50mL) and rinse with 1N sodium hydroxide, saturated sodium chloride, dryover magnesium sulfate, filter and concentrate in vacuo. Purify theresidue by flash chromatography (30% ethyl acetate/hexane) andrecrystallize from ethyl acetate/hexane to yield the title compound (1.0g, 62%).

EXAMPLE 4k

Preparation of 3-3,4-difluorophenacyl)methylamino!-2-carboxy-6-chloroindole ##STR22##

Dissolve 3-(3,4-difluorophenacyl)methylamino!-2-carbmethoxy-6-chloroindole 650 mg,1.7 mmol) in tetrahydrofuran (10 mL) and water (10 mL). Add lithiumhydroxide (227 mg, 5.4 mmol). Add methanol dropwise until an homogeneoussolution forms. Stir the reaction at room temperature overnight. Dilutethe reaction with water(10 mL) and ethyl acetate (25 mL). Acidify with1N HCl and separate the layers. Dry the organic phase over magnesiumsulfate, filter and concentrate 50% with heat. Reconstitute with hothexane. Repeat the concentration and reconstitution steps and cool toyield the title compound (510 mg, 82%); mp 260°-264° C.

Anal. Calcd for C₁₇ H₁₁ ClF₂ N₂ O₃ : C, 55.98; H, 3.04; N, 7.68; Found:C, 56.07; H, 3.06; N, 7.40.

EXAMPLE 4L

Preparation of 3- (phenacyl)methylamino!-2-carboxy-6-fluoroindole##STR23## Step 1. Preparation of starting material:2-amino-4-fluorobenzonitrile;

Suspend 4-fluoro-2-nitro-benzoic acid (4.5 g, 24.3 mmol) in toluene (20mL), add thionyl chloride (22.5 mL) seal the flask and warm to 50° C.for 3 hours. Concentrate the reaction in vacuo and reconcentrate twomore times from toluene. Place under high vacuum for 1 hour. Dissolvethe acid chloride in methylene chloride (40 mL) and add t-butylamine(13.5 mL). Stir the reaction at room temperture. Concentrate thereaction in vacuo to yield the 4-fluoro-2-nitro-tert-butylbenzamide asan off white solid (5.5 g, 95%); mp 142°-143° C.

Anal. Calcd for C₁₁ H₁₃ FN₂ O₃ : C, 55.00; H, 5.45; N, 11.66; Found: C,55.09; H, 5.19; N, 11.63.

Step 2. Dissolve the above product (5 g, 21 mmol) in ethanol (20 mL) andpurge the flask with nitrogen. Add 10% palladium on carbon (200 mg) andplace under hydrogen at 50 psi. Shake the reaction for 2 hours. Filterthe reaction through diatomaceous earth and concentrate the filtrate invacuo. Purify the residue by flash chromatography (25% ethylacetate/hexane) and recrystallize the purified product from ethylacetate/hexane to yield the 4-fluoro-2-amino-tert-butylbenzamide; mp116°-117° C.

Anal. Calcd for C₁₁ H₁₅ FN₂ O: C, 62.84; H, 7.19; N,13.32; Found: C,62.74; H, 6.94; N, 13.08.

Step 3. Dissolve the above product (2.87 g, 14.24 mmol) in methylenechloride (70 mL) and add trifluoroacetic anhydride (10 mL, 71 mmol).Stir the reaction at room temperature for 8 hours under a nitrogenatmosphere. Rinse the reaction with saturated sodium bicarbonate andconcentrate in vacuo. Recrystallize the residue from methylenechloride/hexane to yield the2-trifluoromethylacetamide-4-fluorobenzonitrile as colorless needles(3.2 g, 97%); 104°-105° C.

Anal. Calcd for C₉ H₄ F₄ N₂ O: C, 46.56; H, 1.74; N, 12.07; Found: C,46.67; H, 1.53; N, 12.09.

Scheme I, step a: 2-(Carbethoxy)methylamino-4-fluorobenzonitrile.

Dissolve the 2-trifluoromethylacetamide-4-fluorobenzonitrile (1 g, 4.3mmol) in dimethylformamide (4 mL) under an atmosphere of nitrogen. Addethyl bromoacetate (0.954 mL, 8.6 mmol), potassium carbonate (1.1 g, 8.6mmol) and heat to 50° C. for 2.5 hours. Dilute the reaction with ethylacetate and rinse the organic phase with water. Dry the organic phase,filter and concentrate in vacuo to yield the title compound (1.1 g).

Scheme I, step b: 3-Amino-2-carbethoxy-6-fluoroindole.

Dissolve 2-(Carbethoxy)methylamino-4-fluorobenzonitrile (220 mg, 1 mmol)in tetrahydrofuran (3 mL) and add dropwise with stirring to a solutionof potassium tert-butoxide (1 mL of a 1M solution in 1 mLtetrahydrofuran) under a nitrogen atmosphere. After 1 hour, dilute withethyl acetate, rinse with water, dry the organic phase and concentratein vacuo to yield the title compound (170 mg, 77%).

Scheme I step c: 3- Phenacyl)amino!-2-carbethoxy-6-fluoroindole.

Suspend 3-Amino-2-carbethoxy-6-fluoroindole (1.1 eq) in methylenechloride and add triethylamine (1.1 eq). Add benzoyl chloride (1.1 eq)and stir for 30 minutes at room temperature to produce a precipitate.Dilute the reaction with ethyl acetate, rinse with water, dry overmagnesium sulfate, filter and concentrate in vacuo to yield the titlecompound (1.26 g).

Scheme I, step d₂ : 3-(phenacyl)amino!-2-carbethoxy-6-fluoro-1-(tert-butyloxycarbonyl)-indole.

Mix 3- (phenacyl)amino!-2-carbethoxy-6-fluoroindole (1.0 g, 3.06 mmol),di-tert-butyl dicarbonate (0.70 g, 3.2 mmol), tetrahydrofuran (40 mL),dimethylaminopyridine (33 mg, 0.32 mmol) and stir overnight. Dilute thereaction with ethyl acetate, wash with water, saturated sodium chloride,dry over magnesium sulfate, filter and concentrate in vacuo.Recrystallize from ethyl acetate/hexane followed by flash chromatography(20% ethyl acetate/hexane). Recrystallize again from ethylacetate/hexane to yield 3-(phenacyl)amino!-2-carbethoxy-6-fluoro-1-(tert-butyloxycarbonyl)-indoleas colorless needles (900 mg, 69%).

Scheme I, step: 3-(phenacyl)methylamino!-2-carbethoxy-6-fluoro-1-(tert-butyloxycarbonyl)-indole.

Suspend sodium hydride (62 mg of a 60% dispersion, 1.55 mmol) inanhydrous tetrahydrofuran (3 mL) and cool to 0° C. under a nitrogenatmosphere. Add 3-(phenacyl)amino!-2-carbethoxy-6-fluoro-1-(tert-butyloxycarbonyl)-indole(650 mg, 1.52 mmol) in tetrahydrofuran/dimethylformamide (10 mL, 3:1)dropwise to the suspension producing a clear yellow solution at 15minutes. Stir at 0° C. for 30 minutes. Add methyl iodide (0.096 mL, 1.55mmol). Warm the reaction to room temperature and stir overnight. Quenchwith water (20 mL) and extract with ethyl acetate (20 mL). Rinse theorganic phase with saturated sodium chloride, dry and concentrate invacuo to yield the 3-(phenacyl)methylamino!-2-carbethoxy-6-fluoro-1-(tert-butyloxycarbonyl)-indole.

Scheme I, step f: 3- (phenacyl)methylamino!-2-carbethoxy-6-fluoroindole.

Dissolve 3-(phenacyl)methylamino!-2-carbethoxy-6-fluoro-1-(tert-butyloxycarbonyl)-indolefrom above in methylene chloride (10 mL). Add trifluoracetic acid (3 mL)and stir for 4 hours at room temperture. Dilute with ethyl acetate (50mL) and rinse with 1N sodium hydroxide, saturated sodium chloride, dryover magnesium sulfate, filter and concentrate in vacuo to yield 3-(phenacyl)methylamino!-2-carbethoxy-6-fluoroindole.

Dissolve 3- (phenacyl)methylamino!-2-carbethoxy-6-fluoroindole (300 mg)in tetrahydrofuran and water. Add lithium hydroxide. Stir the reactionat room temperature overnight. Dilute the reaction with water and ethylacetate. Acidify with 1N HCl and separate the layers. Dry the organicphase over magnesium sulfate, filter and concentrate in vacuo.Recrystallize from ethyl acetate/hexane to yield the title compound as awhite powder (270 mg); mp 265°-270° C.

Anal. Calcd for C₁₇ H₁₃ FN₂ O₃ : C, 65.38; H, 4.20; N, 8.97; Found: C,65.25; H, 4.20; N, 8.82.

EXAMPLE 4m

Preparation of 3-(phenacyl)methylamino!-2-carboxy-6-trifluoromethylindole

Step 1. Preparation of starting material: 2-amino-4-trifluoromethylbenzonitrile; Suspend 4-trifluoromethyl-2-nitro-benzoic##STR24## acid (1 g, 4.25 mmol) in toluene (5 mL), add thionyl chloride(5 mL) and reflux for 1.5 hours. Concentrate the reaction in vacuo andreconcentrate two more times from toluene. Place under high vacuum for 1hour. Dissolve the acid chloride in toluene (5 mL) and add excesst-butylamine. Stir the reaction at room temperture. Dilute the reactionwith ethyl acetate and wash with 1M HCl (3×100 mL), dry over magnesiumsulfate, filter and concentrate in vacuo to give a white solid.Recrystallize from hot ethyl acetate/hexane to yield2-nitro-4-trifluoromethyl-tert-butylbenzamide as white crystals (0.96 g,81%); mp 162°-164° C.

Step 2. Dissolve 2-nitro-4-trifluoromethyl-tert-butylbenzamide (520 mg,1.79 mmol) in ethanol (100 mL) and purge the flask with nitrogen. Add 5%palladium on carbon (50 mg) and place under hydrogen at 50 psi. Shakethe reaction for 2 hours. Filter the reaction through diatomaceous earthand concentrate the filtrate in vacuo to yield a white solid. Purify theresidue by flash chromatography (20% ethyl acetate/hexane) to yield the2-amino-4-trifluoromethyl-tert-butylbenzamide as white crystals (280 mg,69% based on recovered starting material); mp 109°-110° C.

Step 3. Dissolve 2-amino-4-trifluoromethyl-tert-butylbenzamide (850 mg,3.26 mmol) in methylene chloride and add trifluoroacetic anhydride (4.62mL, 32.7 mmol). Stir the reaction at room temperature for 6 hours undera nitrogen atmosphere. Rinse the reaction with saturated sodiumbicarbonate, water and concentrate in vacuo to provide an off whitesolid. Recrystallize from ethyl acetate/hexane to yield the2-trifluoromethylacetamide-4-trifluoromethylbenzonitrile (640 mg,69.5%); 118°-119° C.

Scheme I, step a:2-(Carbethoxy)methylamino-4-trifluoromethylbenzonitrile.

Dissolve 2-trifluoromethylacetamide-4-trifluoromethylbenzonitrile (5.44g, 19.28 mmol) in dimethylformamide (30 mL) under an atmosphere ofnitrogen. Add this to a suspension of sodium hydride (848 mg 60%dispersion, 21.21 mmol) in dimethylformamide (2 mL) at 0° C. Warm thesolution to room temperature over 40 minutes. Add ethyl bromoacetate(4.276 mL, 38.6 mmol) to the solution and heat to 50° C. for 40 minutes.Pour the reaction into water and extract with diethyl ether. Separatethe layers and rinse the organic phase with saturated sodium chloride,dry over magnesium sulfate, filter and concentrate in vacuo. Purify theresidue by flash chromatography (50% methanol:chloroform/hexane, 3/2)and recrystallize from hot ethyl acetate/hexane to yield thetrifluoroacetate derivative (5.83 g, 81.7%); mp 79°-80° C.

Dissolve the above carbethoxy derivative (4.9 g, 13.31 mmol) inethanol/water and treat with potassium carbonate (1.837 g, 13.31 mmol).Dilute with water and extract with ethyl acetate. Rinse the organiclayer with saturated sodium chloride, water, dry over magnesium sulfate,filter and concentrate in vacuo to yield a yellow solid. Recrystallizefrom hot ethyl acetate/hexane to yield2-(Carbethoxy)methylamino-4-trifluoromethylbenzonitrile (2.78 g, 76.8%);mp 98°-101° C.

Scheme I, step b: 3-Amino-2-carbethoxy-6-trifluoromethylindole.

Dissolve 2-(Carbethoxy)methylamino-4-trifluoromethylbenzonitrile (2.34g, 8.6 mmol) in tetrahydrofuran (40 mL) and add dropwise with stirringto a solution of potassium tert-butoxide (9.46 mL of a 1Mtetrahydrofuran solution) under a nitrogen atmosphere at 0° C. Thereaction was allowed to warm to room temperature. After 3 hour, dilutewith ethyl acetate, rinse with water, saturated sodium chloride, drymagnesium sulfate, filter and concentrate in vacuo. Purify the residueby flash chromatography to yield the3-amino-2-carbethoxy-6-trifluoromethylindole (1.22 g, 52%); mp 204°-210°C.

Scheme I, step c: 3-(Phenacyl)amino!-2-carbethoxy-6-trifluoromethylindole.

Suspend the 3-amino-2-carbethoxy-6-trifluoromethylindole (290 mg, 1.06mmol) in tetrahydrofuran (30 mL) and add triethylamine (0.150 mL, 1.17mmol). Add benzoyl chloride (0.136 mL, 1.17 mmol) and stir for 30minutes at room temperature. Dilute the reaction with ethyl acetate(mL), rinse with 1M HCl, water, dry over magnesium sulfate, filter andconcentrate in vacuo. Recrystallize from hot ethyl acetate/hexane toyield 3- (phenacyl)amino!-2-carbethoxy-6-trifluoromethylindole (230 mg,56%); mp 237°-239° C.

Scheme I, step d₂ : 3-(phenacyl)amino!-2-carbethoxy-6-trifluoromethyl-1-tert-butyloxycarbonyl)-indole.

Mix 3- (phenacyl)amino!-2-carbethoxy-6-trifluoromethylindole (390 mg,1.04 mmol), di-tert-butyl dicarbonate (249 mg, 1.14 mmol),tetrahydrofuran (10 mL), dimethylaminopyridine (33 mg, 0.32 mmol) andstir overnight. Dilute the reaction with ethyl acetate, wash with 1MHCl, water, dry over magnesium sulfate, filter and concentrate in vacuo.Purify by flash chromatography (15% ethyl acetate/hexane) to yield thetitle compound as an amber oil (320 mg, 66%).

Scheme I, step e: 3-(phenacyl)methylamino!-2-carbethoxy-6-trifluoromethyl-1-(tert-butyloxycarbonyl)-indole.

Suspend sodium hydride (30 mg of a 60% dispersion, 0.739 mmol) inanhydrous tetrahydrofuran (10 mL) and cool to 0° C. under a nitrogenatmosphere. Add 3-(phenacyl)amino!-2-carbethoxy-6-trifluoromethyl-1-(tert-butyloxycarbonyl)-indole(320 mg, 0.672 mmol) in tetrahydrofuran (20 mL) dropwise to thesuspension. Stir at room temperature for 20 minutes. Add methyl iodide(0.0.050 mL, 0.81 mmol). After 3 hours quench with 1M HCl, extract withethyl acetate and rinse the organic phase with saturated sodiumchloride, dry and concentrate in vacuo. Purify the residue by flashchromatography (20% ethyl acetate/hexane) to yield the 3-(phenacyl)methylamino!-2-carbethoxy-6-trifluoromethyl-1-(tert-butyloxycarbonyl)-indoleas a colorless oil (200 mg, 60.6%).

Scheme I, step f: 3-(phenacyl)methylamino!-2-carbethoxy-6-trifluoromethylindole.

Dissolve 3-(phenacyl)methylamino!-2-carbethoxy-6-trifluoromethyl-1-(tert-butyloxycarbonyl)-indole(200 mg, 0.407 mmol) from above in methylene chloride. Addtrifluoracetic acid and stir overnight at room temperture. Concentratethe reaction in vacuo, dilute with ethyl acetate and rinse withsaturated sodium bicarbonate, dry over magnesium sulfate, filter andconcentrate in vacuo to yield 3-(phenacyl)methylamino!-2-carbethoxy-6-trifluoromethylindole as a foam(154 mg, 97%).

Dissolve 3- (phenacyl)methylamino!-2-carbethoxy-6-trifluoromethylindole(154 mg, 0.395 mmol) in tetrahydrofuran and water. Add lithium hydroxide(50 mg, 1.18 mmol). Stir the reaction at room temperature for 6 hours.Acidify with 1N HCl extract with ethyl acetate and separate the layers.Dry the organic phase over magnesium sulfate, filter and concentrate invacuo. Recrystallize from ethyl acetate/hexane to yield the titlecompound as an off white solid (95 mg, 66%); mp 258°-261° C.

Anal. Calcd for C₁₈ H₁₃ F₃ N₂ O₃ H₂ O: C, 56.84; H, 3.98; N, 7.37;Found: C, 56.55; H, 3.74; N, 7.04.

EXAMPLE 4n

Preparation of 3- (phenacyl)methylamino!-2-carboxy-6-nitroindole##STR25##

Step 1. Preparation of starting material: 2-amino-4-nitrobenzonitrile;Dissolve 4-nitro-2-aminobenzoic acid (500 mg, 2.75 mmol) intetrahydrofuran (10 mL). Add triphenylphosphine (730 mg, 2.75 mL) andN-hydroxysuccinimide (316 mg, 2.75 mmol). Add a solution ofdiethylazodicarboxylate (0,433 mL,2.75 mmol) and stir at roomtemperature under nitrogen for 10 minutes. Add tert-butylamine (1.1 mL,5.5 mmol) in tetrahydrofuran (5 mL) directly to the reaction to yieldafter workup the 4-nitro-2-amino-tert-butylbenzamide.

Step 2: Dissolve the above product (300 mg, 1.31 mmol) in methylenechloride and add trifluoroacetic anhydride (3 mL, 6.5 mmol). Stir thereaction at room temperature overnight. Rinse the reaction withsaturated sodium bicarbonate, water and concentrate in vacuo. Purify byflash chromatography (25% ethyl acetate/hexane) to yield the2-trifluoromethylacetamide-4-nitrobenzotrile (250 mg, 73%).

Scheme I, step a: 2-(Carbethoxy)methylamino-4-nitrobenzonitrile.

Dissolve 2-trifluoromethylacetamide-4-nitrobenzotrile (250 mg, 0.96mmol) in dimethylformamide (0.5 mL). Add ethyl bromoacetate (0.222 mL, 2mmol), potassium carbonate (260 mg, 2 mmol) and warm to 80° C. for 2hours. Cool the reaction, dilute with ethyl acetate, rinse with water,dry, filter and concentrate in vacuo. Purify the residue by flashchromatography (25% ethyl acetate/hexane) to yield the trifluoroacetatederivative (170 mg).

Dissolve the above product(0.8 mmol) in ethanol/water and treat withpotassium carbonate (0.8 mmol). Dilute with water and extract with ethylacetate. Rinse the organic layer with saturated sodium chloride, water,dry over magnesium sulfate, filter and concentrate in vacuo to yield ayellow solid. Recrystallize from hot ethyl acetate/hexane to yield2-(Carbethoxy)methylamino-4-nitrobenzonitrile.

Scheme I, step b: 3-Amino-2-carbethoxy-6-nitroindole.

Dissolve the above carbethoxy derivative (0.7 mmol) in tetrahydrofuranand add dropwise with stirring to a solution of potassium tert-butoxide(0.7 mL of a 1M tetrahydrofuran solution) under a nitrogen atmosphere at0° C. The reaction was allowed to warm to room temperature. After 3hour, dilute with ethyl acetate, rinse with water, saturated sodiumchloride, dry magnesium sulfate, filter and concentrate in vacuo. Purifythe residue by flash chromatography to yield the the3-amino-2-carbethoxy-6-nitroindole.

Scheme I, step c: 3- (phenacyl)amino!-2-carbethoxy-6-nitroindole.

Suspend the 3-amino-2-carbethoxy-6-nitroindole (0.6 mmol) intetrahydrofuran (mL) and add triethylamine (0.62 mmol). Add benzoylchloride (0.62 mmol) and stir for 30 minutes at room temperature. Dilutethe reaction with ethyl acetate, rinse with 1M HCl, water, dry overmagnesium sulfate, filter and concentrate in vacuo. Recrystallize fromhot ethyl acetate/hexane to yield 3-(phenacyl)amino!-2-carbethoxy-6-nitroindole.

Scheme I, step d₂ : 3-(phenacyl)amino!-2-carbethoxy-6-nitro-1-(tert-butyloxycarbonyl)-indole.

Mix 3- (phenacyl)amino!-2-carbethoxy-6-nitroindole (0.5 mmol),di-tert-butyl dicarbonate (0.52 mmol), tetrahydrofuran,dimethylaminopyridine (mg, mmol) and stir overnight. Dilute the reactionwith ethyl acetate, wash with 1M HCl, water, dry over magnesium sulfate,filter and concentrate in vacuo to yield the 3-(phenacyl)amino!-2-carbethoxy-6-nitro-1-(tert-butyloxycarbonyl)-indole.

Scheme I, step e: 3-(phenacyl)methylamino!-2-carbethoxy-6-nitro-1-(tert-butyloxycarbonyl)-indole.

Suspend sodium hydride (0.4 mmol) in anhydrous tetrahydrofuran and coolto 0° C. under a nitrogen atmosphere. Add 3-(phenacyl)amino!-2-carbethoxy-6-nitro-1-(tert-butyloxycarbonyl)-indole(0.4 mmol) in tetrahydrofuran (mL) dropwise to the suspension. Stir atroom temperature for 20 minutes. Add methyl iodide (0.4 mmol). After 3hours quench with 1M HCl, extract with ethyl acetate and rinse theorganic phase with saturated sodium chloride, dry and concentrate invacuo to yield the 3-(phenacyl)methylamino!-2-carbethoxy-6-nitro-1-(tert-butyloxycarbonyl)-indole.

Scheme I, step f: 3- (phenacyl)methylamino!-2-carbethoxy-6-nitroindole.

Dissolve 3-(phenacyl)methylamino!-2-carbethoxy-6-nitro-1-(tert-butyloxycarbonyl)-indolefrom above in methylene chloride. Add excess trifluoracetic acid andstir overnight at room temperture. Concentrate the reaction in vacuo,dilute with ethyl acetate and rinse with saturated sodium bicarbonate,dry over magnesium sulfate, filter and concentrate in vacuo to yield 3-(phenacyl)methylamino!-2-carbethoxy-6-nitroindole.

Dissolve 3- (phenacyl)methylamino!-2-carbethoxy-6-nitroindole 0.3 mmol)in tetrahydrofuran and water. Add lithium hydroxide (0.9 mmol). Stir thereaction at room temperature for 6 hours. Acidify with 1N HCl extractwith ethyl acetate and separate the layers. Dry the organic phase overmagnesium sulfate, filter and concentrate to yield the title compound.

EXAMPLE 5

Preparation of 3- (Phenacyl)amino!-2-(2-dimethylamino)carbethoxy!-6-chloroindole ##STR26##

Mix 3- (phenacyl)amino!-2-carbmethoxy-6-chloroindole (1.0 g, 3.04 mmol)with 2-dimethylaminoethanol (5 mL), potassium carbonate (3.04 mmol) andtoluene (25 mL) and warm at 70° C. for hours. Cool and apply to a silicagel column and elute with 5% methanol/chloroform. Evaporate the solventto 150 mL and add hot hexane (200 mL). Cool and filter to give the titlecompound as a white powder (700 mg, 64%).

EXAMPLE 6

Preparation of 3- Methyloxalylate)amino!-2-carbmethoxyindole ##STR27##Step a: 2- (Carbmethoxy)methylamino!-2-benzonitrile

Dissolve 2-aminobenzonitrile (10 g, 85 mmol) in methanol (20 mL). Addsodium hydrogen carbonate (7.6 g, 90 mmol) and methyl bromoacetate (8.5mL, 90 mmol) and heat at reflux overnight. Cool and filter. Evaporatethe solvent in vacuo and purify by flash chromatography (25% ethylacetate/hexane). Recrystallize (ethyl acetate/hexane) to give the titlecompound as white crystals; first crop (6 g, 37%) and second crop (3 g,18%); mp 86°-88° C.

Step b: 3-Amino-2-carmethoxy-indole

Dissolve potassium tert-butoxide (31.5 mmol) in anhydroustetrahydrofuran (31.5 mL) and cool to 5° C. Add a solution of2-(carmethoxy)methylaminobenzonitrile (6 g, 31.5 mmol) in anhydroustetrhydrofuran. Allow to warm to room temperature and stir for 3 hours.Pour into water/ethyl acetate, separate the organic phase and dry(MgSO₄). Evaporate the solvent in vacuo and purify by flashchromatography (25% ethyl acetate/hexane) and recrystallize (25% ethylacetate/hexane then adding hexane until needles appear) to give thetitle compound; first crop (2.3 g, 38%) and second crop (0.5 g, 8.3%);mp 128°-135° C. (dec).

Step c: 3- (Methyloxalylate)amino!-2-carbmethoxy-indole

Dissolve 3-amino-2-carbmethoxy-indole (250 mg, 1.31 mmol) in methylenechloride (3 mL). Add triethylamine (182 μL, 1.31 mmol), followed by slowaddition of methyl chlorooxalate (120 μL, 1.31 mmol). Stir at roomtemperature briefly. Dilute with water and ethyl acetate, separate theorganic phase and dry (MgSO₄). Evaporate the solvent in vacuo anddissolve the residue in hot ethyl acetate (40 mL). Reduce the volume to20 mL and add hot hexane (20 mL). Cool and collect the title compound asbright yellow needles; first crop (290 mg, 84%) and second crop (39 mg,11%); mp 217°-19° C.

EXAMPLE 7

Preparation of 3- (Oxalyl)amino!-2-carboxy-indole ##STR28##

Dissolve 3- (methyloxalylate)amino!-2-carbmethoxy-indole (200 mg, 0.72mmol) in methanol (10 mL). Add sodium hydroxide (3.62 mL of a 1Nsolution in water, 3.62 mmol) and warm to 40° C. for 1 hour. Dilute withwater (50 mL), acidify and extract into ethyl acetate. Separate theorganic phase, dry (MgSO₄) and evaporate the solvent in vacuo to givethe title compound as a yellow powder (84%); mp 200°-04° C.

An alternate synthetic procedure for preparing appropriate startingmaterials for compounds of Formula I is set forth in Scheme V. In SchemeV, all substituents, unless otherwise indicated, are as previouslydefined. ##STR29##

In step a, an appropriate 2-carbalkoxy-indole of structure (28) can benitrated to produce the 2-carbalkoxy-3-nitro-indole of structure (29).

The nitration reaction of step a can be carried out using techniquesknown in the art. Typically, the 2-carbalkoxy-indole as described bystructure (14) is contacted with a large excess of fuming nitric acid.The reactants are typically contacted in an acidic medium, such asacetic acid. The reactants are typically stirred for a period of timeranging from 10 minutes to 4 days and at a temperature range of from 0°C. to room temperature. The 2-carbalkoxy-3-nitro-indole of structure(29) can be recovered from the reaction by precipitation with waterfollowed by filtration.

In step b, the nitro functionality of the appropriate2-carbalkoxy-3-nitro-indole of structure (29) can be reduced to thecorresponding amino functionality to produce the3-amino-2-carbalkoxy-indole of structure (4).

The reduction reaction of step b can also be carried out usingtechniques known in the art. Typically, the 2-carbalkoxy-3-nitro-indoleof structure (29) is contacted with 5 equivalents of tin (II) chloridedihydrate. The reactants are typically contacted in an organic solventsuch as ethanol. The reactants are typically stirred together for aperiod of time ranging from 1-24 hours and at a temperature range fromabout room temperature to reflux. The 3-amino-2-carbalkoxy-indole ofstructure (4) can be recovered from the reaction by techniques such asflash chromatography.

Compounds of Formula I can be prepared from the appropriate3-amino-2-carbalkoxy-indole of structure (4) as described previously inScheme I, steps c-g. Side-chain functionality may also be manipulated asdescribed previously in Scheme I.

Starting materials for use in the general synthetic procedure outling inScheme V are readily available to one of ordinary skill in the art anddescribed previously in Scheme I.

The following examples present typical syntheses as described in SchemeV. These examples are understood to be illustrative only and are notintended to limit the scope of the present invention in any way.

EXAMPLE 8

Preparation of 3- (Phenacyl)amino!-2-carbethoxy-4,6-dichloroindole##STR30## Step a: 3-Nitro-2-carbethoxy-4,6-dichloroindole

Dissolve 3,5-dichlorophenylhydrazine hydrochloride (300 g) in anhydrousethanol (2 L). Add ethyl pyruvate (153.6 mL) and concentrated sulfuricacid (25 mL). Stir at room temperature under a nitrogen atmosphere for 3hours. Evaporate the solvent in vacuo, take up the residue in ethylacetate/water and treat with saturated sodium hydrogen carbonate.Separate the aqueous phase and extract with ethyl acetate. Combine theorganic phases, dry (MgSO₄) and evaporate the solvent in vacuo to givethe 3,5-dichlorophenylhydrazone of ethyl pyruvate and as a solid (371.6g, 96%). Both E and Z isomers are obtained.

¹ H NMR (CDCl₃), 90 MHz) isomer A, δ11.9 (b, 1H), 7.0 (d, 2H), 6.8 (d,1H), 4.2 (q, 2H), 2.1 (s, 3H), 1.3 (t, 3H); isomer B δ7.9 (b, 1H),7.2-6.8 (m, 3H), 4.3 (q, 2H), 2.1 (s, 3H), 1.4 (t, 3H).

Add polyphosphoric acid (2 kg) to the 3,5-dichlorophenylhydrazone ofethyl pyruvate (100 g) and heat on a steam bath for 5 hours. Add a smallamount of ice and pour onto ice to decompose the polyphosphoric acid.Extract the resulting suspension into ethyl acetate (3×1 L) and dry(MgSO₄). Evaporate the solvent in vacuo to give a light brown solid.Stir the solid with ethyl ether (1 L) for 1 hour and filter off2-carboxyethyl-4,6-dichloroindole. Heat the filtrate with activatedcharcoal, filter through Celite and evaporate the solvent in vacuo togive a second crop of 2-carboxyethyl-4,6-dichloroindole as a tan solid(89.4 g total, 95%).

IR (KBr) 3406, 3314, 1698, 1568, 1324, 1244, 1214, 840, and 770 cm⁻¹

¹ H-NMR (DMSO-d₆, 300 MHz) δ12.4 (b, 1H), 7.5 (s, 1H), 7.3 (s, 1H), 7.1(s, 1H), 4.4 (q, 2H, J=7 Hz), 1.4 (t, 3H, J=7 Hz); 13C-NMR (DMSO-d₆, 75MHz) δ160.6, 137.6, 129.2, 129.1, 126.9, 124.3, 120.0, 111.4, 105.3,61.0, 14.2; MS (CI/CH₄) m/z 258 (M+H)⁺ ;

Anal. Calcd for C₁₁ H₉ Cl₂ NO₂ : C, 51.19; H, 3.51; N, 5.43; Found: C,51.38, H, 3.42; N, 5.53.

Mix 2-carboxyethyl-4,6-dichloroindole (50 g) and acetic acid (1 L) andadd, by dropwise addition, 90% (white fuming) nitric acid (250 mL).Apply a water bath as necessary to keep the temperature below 29° C.Stir for 10 minutes after all of the solid is dissolved and pour intoice (6 L). Filter off the solid and wash with water. Dissolve the solidin ethyl acetate, treat with saturated sodium hydrogen carbonatesolution, and separate the organic phase. Dry (MgSO₄), filter andevaporate the solvent in vacuo to give the crude product as a tan solid.Slurry the solid in a small amount of chloroform, filter and dry to givethe title compound (36.9 g, 63%).

Step b: 3-Amino-2-carbethoxy-4,6-dichloroindole

Dissolve 3-nitro-2-carbethoxy-4,6-dichloroindole (38.1 g) in ethanol (1L) and add tin (II) chloride dihydrate (163 g). Warm to between 65° and75° C. for 4 to 5 hours. Cool to room temperature and pour into amixture of ethyl acetate (3 L) and water (2 L). Add solid potassiumcarbonate and stir occasionally until the carbon dioxide evolutionceases. Filter throught Celite and separate the organic phase of thefiltrate. Dry (MgSO₄) and evaporate the solvent in vacuo to give thetitle compound as an off-yellow solid (33.5 g, 97.6%).

Scheme I, step c: 3- (Phenacyl)amino!-2-carbethoxy-4,6-dichloroindole

Dissolve 3-amino-2-carbethoxy-4,6-dichloroindole (7.8 g, 27.8 mmol) inmethylene chloride (500 mL) and add triethylamine (4.2 mL, 30 mmol)followed by benzoyl chloride (3.5 mL, 30 mmol). Stir at room temperatureovernight. Dilute with ethyl acetate (300 mL), wash with water andseparate the organic phase. Dry (MgSO₄) and evaporate the solvent invacuo to give a solid. Recrystallize (ethyl acetate) to give the titlecompound as off-white needles (7.75 g, 74%).

EXAMPLE 9

Preparation of 3- (Phenacyl)amino!-2-carboxy-4,6-dichloroindole##STR31##

Mix 3- (Phenacyl)amino!-2-carbethoxy-4,6-dichloroindole (300 mg, 0.79mmol), lithium hydroxide monohydrate (2.39 mmol), tetrahydrofuran (2 mL)and water (2 mL). Stir at room temperature overnight. Dilute with waterand ethyl acetate. Acidify the aqueous phase and separate the organicphase. Dry (MgSO₄), evaporate the solvent in vacuo, and recrystallizethe residue (ethyl acetate/hexane) to to give the title compound (175mg, 64%).

EXAMPLE 10

Preparation of 3- (Phenacyl)methylamino!-2-carbethoxy-4,6-dichloroindole##STR32## Scheme I, step d₂ : 3-(Phenacyl)amino!-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole

Mix 3- (phenacyl)amino)!-2-carbethoxy-4,6-dichloroindole (6 g, 16 mmol),di-tert-butyl dicarbonate (3.5 g, 16 mmol), tetrahydrofuran (90 mL) anddimethylaminopyridine (85 mg, 0.8 mmol) and stir at room temperature for1 hour. Dilute with ethyl acetate, wash with water and separate theorganic phase. Dry (MgSO₄) and evaporate the solvent in vacuo.Recrystallize the residue (ethyl acetate/hexane) to give the titlecompound as white crystals (7.0 g, 92%); mp 143°-4° C.

Scheme I, step e: 3-(Phenacyl)methylamino!-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole

Suspend sodium hydride (20 mg of a 60% dispersion, 0.5 mmol) inanhydrous tetrahydrofuran (1 mL) and cool to 0° C. under a nitrogenatmosphere. Slowly add 3-(phenacyl)amino!-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole(220 mg, 0.46 mmol) in tetrahydrofuran (1 mL). Stir at 0° C. for 0.5hours. Add methyl iodide (31 uL, 0.5 mmol) and stir at 0° C. for 2hours. Quench with water, extract into ethyl acetate and separate theorganic phase. Dry (MgSO₄) and evaporate the solvent in vacuo. Purifythe residue by flash chromatography (25% ethyl acetate/hexane) andrecrystallize (hexane) to give the title compound (2.9 g, 95%); mp130°-1° C.

Scheme I, step f: 3-(Phenacyl)methylamino!-2-carbethoxy-4,6-dichloroindole

Dissolve 3-(phenacyl)methylamino!-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole(2.8 g, 5.7 mmol) in methylene chloride (5 mL). Add trifluoroacetic acid(5 mL) and stir for 1 hour. Evaporate to dryness in vacuo andrecrystallize the residue (ethyl acetate/hexane) to give the titlecompound as white needles (1.8 g, 82%); mp 195°-97° C.

EXAMPLE 11

Preparation of 3- (Phenacyl)methylamino!-2-carboxy-4,6-dichloroindole##STR33##

Dissolve 3- (phenacyl)methylamino!-2-carbethoxy-4,6-dichloroindole (800mg, 2.04 mmol) in tetrahydrofuran (5 mL) and water (5 mL). Add lithiumhydroxide monohydrate (252 mg, 6 mmol) and stir at room temperatureovernight. Warm to 50° C. in an water bath for several hours, dilutewith water (10 mL) and ethyl acetate (25 mL). Stir and acidify with 1Nhydrochloric acid. Separate the organic phase and dry. Evaporate thesolvent in vacuo and recrystallize (ethyl acetate/hexane) to give thetitle compound as a white powder (630 mg, 85%); mp 275° C. (dec).

EXAMPLE 11a

Preparation of 3- (Phenacyl)methylamino!-2-tetrazole-4,6-dichloroindole##STR34##

Scheme II, step a: Suspend 3-(Phenacyl)methylamino!-2-carboxy-4,6-dichloroindole(4.25 mmol) intoluene (5 mL), add thionyl chloride (5 mL) and reflux for 1.5 hours.Concentrate the reaction in vacuo and reconcentrate two more times fromtoluene. Place under high vacuum for 1 hour. Dissolve the acid chloridein toluene (5 mL) and add excess t-butylamine. Stir the reaction at roomtemperture. Dilute the reaction with ethyl acetate and wash with 1M HCl(3×100 mL), dry over magnesium sulfate, filter and concentrate in vacuoto yield the tert-butylamide.

Scheme II, step b: Dissolve the above tert-butylamide derivative (3.26mmol) in methylene chloride and add trifluoroacetic anhydride (32.7mmol). Stir the reaction at room temperature for 6 hours under anitrogen atmosphere. Rinse the reaction with saturated sodiumbicarbonate, water and concentrate in vacuo to yield the 2-cyanoindolylderivative.

Scheme III, step c: Dissolve the above 2-cyanoindolyl derivative (3mmol) in N-methylpyrrolidinone (5 mL) and treat with tributyltinchloride (3.24 mmol), sodium azide (3 mmol) and heat to 70° C. for 3days. Dilute the reaction with an addtional amount ofN-methylpyrrolidinone (5 mL) and allow to cool. Add 1N HCl (5 mL) andextract with ethyl acetate. Dry the organic phase over sodium sulfate,filter and concentrate in vacuo to yield the title compound.

EXAMPLE 11b

Preparation of 3- (tetrazoleacyl)amino!-2-carboxy-4,6-dichloroindole##STR35##

Scheme III, step a: Combine3-amino-2-carb-tert-butoxy-4,6-dichloroindole (5 mmol), triethylamine(5.5 mmol) and methylene chloride (100 mL). Add methyl oxalyl chloride(5.5mmol) and stir at room temperature for 4 hours. Pour the reactioninto saturated sodium bicarbonate and separate the layers. Wash theorganic phase with saturated sodium chloride, dry over magnesiumsulfate, filter and concentrate in vacuo to yield the 3-amidoindolylderivative.

Scheme III, step d: Dissolve the above aminoindolyl derivative (3.2mmol) in tetrahydrofuran and water (1:1) and treat with lithiumhydroxide (3.2 mmol). Stir the reaction for 6 hours, carefully acidifyto pH 5 and immediately extract the aqueous with ethyl acetate. Dry theorganic phase with magnesium sulfate, filter and concentrate in vacuo toyield the monoacid.

Scheme III, step e: Dissolve the above monoacid (3 mmol) intetrahydrofuran and treat with triphenyphosphine (3 mmol),diethylazodicarboxylate (3 mmol) followed by N-hydroxysuccinimide atroom temperature. Stir for 1 hour and then treat the reaction withtert-butylamine (3 mmol). Stir for an additional 2 hours at roomtemperature and dilute with water. Extract the aqueous with ethylacetate, dry the organic phase over magnesium sulfate, filter andconcentrate in vacuo to afford the tert-butylamide derivative.

Scheme III, step f: Dissolve the above tert-butylamide derivative (3mmol) in methylene chloride and add trifluoroacetic anhydride (30 mmol).Stir the reaction at room temperature for 6 hours under a nitrogenatmosphere. Rinse the reaction with saturated sodium bicarbonate, waterand concentrate in vacuo to yield the cyano derivative.

Scheme III, step g: Dissolve the above cyano derivative (3 mmol) inN-methylpyrrolidinone (5 mL) and treat with tributyltin chloride (3.24mmol), sodium azide (3 mmol) and heat to 70° C. for 3days. Dilute thereaction with an additional amount of N-methylpyrrolidinone (5 mL) andallow to cool. Add 1N HCl (5 mL) and extract with ethyl acetate. Dry theorganic phase over sodium sulfate, filter and concentrate in vacuo toyield the tetrazole derivative.

Scheme III, step h: Dissolve the above tetrazole derivative (3 mmol) inmethylene chloride (20 mL). Add trifluoroacetic acid (2 mL) and stir atroom temperature for 3 hours. Dilute the reation with water (20 mL) andseparate the layers. Dry the organic phase over magnesium sulfate,filter and concentrate in vacuo to yield the title compound.

EXAMPLE 11c

Preparation of 3-(tetrazoleacyl)amino!-2-carbotetrazole-4,6-dichloroindole ##STR36##

Scheme III, step e: Suspend 3-(tetrazoleacyl)amino!-2-carboxy-4,6-dichloroindole (3 mmol) in toluene(5 mL), add thionyl chloride (5 mL) and reflux for 1.5 hours.Concentrate the reaction in vacuo and reconcentrate two more times fromtoluene. Place under high vacuum for 1 hour. Dissolve the acid chloridein toluene (5 mL) and add excess t-butylamine. Stir the reaction at roomtemperture. Dilute the reaction with ethyl acetate and wash with 1M HCl(3×100 mL), dry over magnesium sulfate, filter and concentrate in vacuoto yield the tert-butylamide.

Scheme III, step f: Dissolve the above tert-butylamide derivative (3mmol) in methylene chloride and add trifluoroacetic anhydride (30 mmol).Stir the reaction at room temperature for 6 hours under a nitrogenatmosphere. Rinse the reaction with saturated sodium bicarbonate, waterand concentrate in vacuo to yield the 2-cyanoindolyl derivative.

Scheme III, step g: Dissolve the above 2-cyanoindolyl derivative (3mmol) in N-methylpyrrolidinone (5 mL) and treat with tributyltinchloride (3.24 mmol), sodium azide (3 mmol) and heat to 150° C. for 4hours. Dilute the reaction with an additional amount ofN-methylpyrrolidinone (5 mL) and allow to cool. Add 1N HCl (5 mL) andextract with ethyl acetate. Dry the organic phase over sodium sulfate,filter and concentrate in vacuo to yield the title compound.

EXAMPLE 12

Preparation of 3-(Phenacyl)methylamino!-2-sodium-carboxylate-4,6-dichloroindole ##STR37##

Suspend 3- (phenacyl)methylamino!-2-carboxy-4,6-dichloroindole (0.98 g,2.7 mmol) in water and add sodium hydroxide (11 mL of a 0.25M solution)and heat the partial solution until a pale yellow solution is obtained.Filter and freeze-dry to give the title compound (1.01 g, 97.3%) as awhite powder.

Anal. Calcd for C₁₇ H₁₁ Cl₂ N₂ O₃.H₂ O₃.Na: C, 50.64; H, 3.25; N, 6.95;Found: C, 50.75; H, 2.93; N, 6.86.

EXAMPLE 13

Preparation of 3- (Phenacyl)methylamino!-2-2-dimethylamino)-carbethoxy!-4,6-dichloroindole ##STR38##

Mix 3- (phenacyl)amino!-2-carbethoxy-4,6-dichloroindole (1 g, 2.56mmol), 2-dimethylaminoethanol (5 mL), potassium carbonate (353 mg, 2.56mmol) and toluene (15 mL). Heat at 70° C. overnight. Purify by flashchromatography (5% methanol/chloroform) and recrystalize (ethylacetate/hexane) to give the title compound (600 mg, 54%); mp 171°-2° C.

EXAMPLE 14

Preparation of 3- (Phenacyl)ethylamino!-2-carbethoxy-4,6-dichloroindole##STR39## Scheme I, step e: 3-(Phenacyl)ethylamino!-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole

Suspend sodium hydride (52 mg of a 60% dispersion, 1.73 mmol) inanhydrous dimethylformamide and cool to -10° C. Add, by dropwiseaddition, a solution of 3-(phenacyl)amino!-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole(0.75 g, 1.57 mmol) in dimethylformamide. Stir under a nitrogenatmosphere for 30 minutes. Add ethyl iodide (0.27 g, 1.73 mmol) and stirat -10° C. for 5 hours. Pour into 1N hydrochloric acid (100 mL) andextract into ethyl acetate. Separate the organic phase and dry (MgSO₄).Evaporate the solvent in vacuo and purify by flash chromatography (4:1methylene chloride/ethyl acetate and recrystallize (ethylacetate/hexane) to give the title compound; mp 110°-11° C.

Scheme I, step f: 3-(Phenacyl)ethylamino!-2-carbethoxy-4,6-dichloroindole

Dissolve 3-(phenacyl)ethylamino!-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole(0.79 g, 1.57 mmol) in methylene chloride (5 mL) and add, by dropwiseaddition, trifluoroacetic acid (5 mL). Stir for 4 hours and pourcarefully into saturated sodium hydrogen carbonate (100 mL). Extractinto ethyl acetate, dry (MgSO₄) and evaporate the solvent in vacuo togive as yellow oil. Recrystallize (ethyl acetate/hexane) to give thetitle compound (0.23 g, 36%); mp 203°-5° C.

EXAMPLE 15

Preparation of 3- (Phenacyl)ethylamino!-2-carboxy-4,6-dichloroindole##STR40##

Mix 3- (phenacyl)ethylamino!-2-carbethoxy-4,6-dichloroindole (600 mg,1.48 mmol), water (10 mL) and tetrahydrofuran (10 mL). Add lithiumhydroxide monohydrate (0.22 g, 5.18 mmol) and stir at room temperaturefor 24 hours. Heat to reflux for 5 hours then pour into 1N hydrochloricacid (100 mL). Extract into ethyl acetate, dry (MgSO₄) and evaporate thesolvent in vacuo to give the crude product (0.72 g) as a white solid.Recrystallize (ethyl acetate/hexane) to give the title to compound (0.32g, 57%); mp 254°-6° C.

EXAMPLE 16

Preparation of 3- (Phenacyl)benzylamino!-2-carbethoxy-4,6-dichloroindole##STR41## Scheme I, step e: 3-(Phenacyl)benzylamino!-2-carbethoxy-4,6-dichloro-1-tert-butloxyycarbonyl-indole

Suspend sodium hydride (42 mg of a 60% dispersion, 1.39 mmol) indimethylformamide, place under nitrogen atmosphere and cool to -10° C.Add, by dropwise addition, a solution of 3-(phenacyl)amino!-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole(0.6 g, 1.26 mmol) in dimethylformamide. Stir at -10° C. for 30 minutesand add, by dropwise addition, benzyl bromide (0.24 g, 1.39 mmol). Stirfor 5 hours, pour into 1N hydrochloric acid and extract into ethylacetate. Dry (MgSO₄) and evaporate the solvent in vacuo to give thetitle compound as a yellow oil.

Scheme I, step f: 3-(Phenacyl)benzylamino!-2-carbethoxy-4,6-dichloroindole

Dissolve 3-(phenacyl)benzylamino!-2-carbethoxy-2,6-dichloro-1-tert-butyloxycarbonyl-indole(0.68 g, 1.26 mmol) in methylene chloride (5 mL) and add, by dropwiseaddition, trifluoroacetic acid (5 mL). Stir for 4 hours then slowly addto saturated sodium hydrogen carbonate (100 mL). Extract into methylenechloride, dry (MgSO₄) and evaporate the solvent in vacuo. Recrystallize(ethyl acetate/hexane) to give the title compound (0.34 g, 59%); mp174°-5° C.

EXAMPLE 17

Preparation of 3- (Phenacyl)benzylamino!-2-carboxy-4,6-dichloroindole##STR42##

Dissolve 3- (phenacyl)benzylamino!-2-carbethoxy-4,6-dichloroindole (0.5g, 1.07 mmol) in tetrahydrofuran (10 mL) and water (10 mL). Add lithiumhydroxide monohydrate (0.16 g, 3.74 mmol) and stir for 24 hours. Heat atreflux for 6 hours and pour into 1N hydrochloric acid (100 mL). Extractinto ethyl acetate, dry (MgSO₄) and evaporate the solvent in vacuo.Recrystallize (ethyl acetate/hexane) to give the title compound; mp266°-7° C.

EXAMPLE 18

Preparation of 3-(Phenacyl)carbethoxymethyl-amino!-2-carbethoxy-4,6-dichloroindole##STR43## Scheme I, step e: 3-(Phenacyl)carbethoxymethyl-amino!-2-carbethoxy-4,6-chloro-1-tert-butyloxycarbonyl-indole

Suspend sodium hydride (29.3 mg of a 60% dispersion, 0.976 mmol) indimethylformamide (2 mL), place under nitrogen atmosphere and cool to 0°C. Add, by dropwise addition, a solution of 3-(phenacyl)amino!-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole(0.42 g, 0.887 mmol) in dimethylformamide (3 mL). Stir for 2 hours,dilute with ethyl acetate (100 mL) and wash with 1N hydrochloric acid.Dry (MgSO₄) and evaporate the solvent in vacuo to give 0.58 g crudeproduct. Recrystallize (ethyl acetate/hexane) to give the title compound(0.36 g, 72%); mp 129°-30° C.

Scheme I, step f: 3-(Phenacyl)carbethoxymethyl-amino!-2-carbethoxy-4,6-dichloroindole

Dissolve 3-(phenacyl)carbethoxymethyl-amino!-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole(0.4 g, 0.71 mmol) in methylene chloride (6 mL) and add, by dropwiseaddition, trifluoroacetic acid (6 mL). Stir for 3.5 hours and pourslowly into saturated sodium hydrogen carbonate (100 mL). Extract withethyl acetate and dry (MgSO₄). Evaporate the solvent in vacuo andrecrystallize the residue (ethyl acetate/hexane) to give the titlecompound (0.28 g, 85%); mp 139°-40° C.

EXAMPLE 19

Preparation of 3-(Phenacyl)carboxymethyl-amino!-2-carboxy-4,6-dichloroindole ##STR44##

Dissolve 3-(phenacyl)carbethoxymethyl-amino!-2-carbethoxy-4,6-dichloroindole (0.29g, 0.626 mmol) in tetrahydrofuran (27 mL) and water (13 mL). Add lithiumhydroxide monohydrate (0.158 g, 3.76 mmol) and stir overnight. Pour into1N hydrchloric acid (100 mL) and extract into ethyl acetate. Dry (MgSO₄)and evaporate the solvent in vacuo. Recrystallize (ethyl acetate/hexane)to give the title compound (0.15 g, 59% mp 235°-7° C.

EXAMPLE 20

Preparation of 3-(2-Benzylphenacyl)amino!-2-carbethoxy-4,6-dichloroindole ##STR45##

Mix 3-amino-2-carbethoxy-2,6-dichloroindole (2.73 g, 10 mmol), 2-benzylbenzoyl chloride (10 mmol) in pyridine (50 mL) and heat at 60° C. for 48hours. Pour into water, separate the organic phase and wash with 1Nhydrochloric acid, then with saturated sodium hydrogen carbonate. Dry(MgSO₄) and evaporate the solvent in vacuo. Purify by flashchromatography (25% ethyl acetate/hexane) and recrystallize (ethylacetate/hexane) to give the title compound (450 mg); mp 225°-227° C.

Anal. Calcd for C₂₅ H₂₀ Cl₂ N₂ O₃ : C, 64.25; H, 4.31; N, 5.99; Found:C, 63.91; H, 4.42; N, 6.12.

EXAMPLE 21

Preparation of 3- (2-Benzylphenacyl)amino!-2-carboxy-4,6-dichloroindole##STR46##

Dissolve 3- (2-benzylphenacyl)amino!-2-carbethoxy-4,6-dichloroindole(100 mg, 0.214 mmol) in tetrahydrofuran (7 mL) and water (7 mL). Addlithium hydroxide monohydrate (25.2 mg, 6 mmol) and stir overnight. Stirat 40° C. for 2 hours, dilute with water (10 mL) and ethyl acetate (25mL). Acidify with 1N hydrochloric acid while stirring. Separate theorganic phase, dry (MgSO₄) and evaporate the solvent in vacuoRecrystallize (ether/hexane) to give the title compound (89 mg, 95%); mp234°-235° C.

Anal. Calcd for C₂₃ H₁₆ Cl₂ N₂ O₃ : C, 62.88; H, 3.67; N, 6.38; Found:C, 63.04; H, 4.05; N, 5.97.

EXAMPLE 22

Preparation of 3-(2-Benzylphenacyl)methylamino!-2-carbethoxy-4,6-dichloroindole ##STR47##Scheme I step d₂ : 3-2-Benzylphenacyl)amino!-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole

Dissolve 3-(2-benzylphenacyl)amino!-2-carbethoxy-4,6-dichlorocarbonylindole (400mg, 0.856 mmol) in tetrahydrofuran (40 mL). Add di-tert-butyldicarbonate (0.9 mmol) and dimethylaminopyridine (10 mg). Stir for 2hours and partition between ethyl acetate and water. Separate theorganic phase, dry (MgSO₄) and evaporate the solvent in vacuo.Recrystallize (ethyl acetate/hexane) to give the title compound (420 mg,86%) as a white solid; mp 163° C.

Scheme I, step e: 3-(2-Benzylphenacyl)methylamino!-2-carbethoxy-4,6-chloro-1-tert-butyloxycarbonyl-indole

Suspend sodium hydride (32 mg of a 60% dispersion, 0.8 mmol) inanhydrous dimethylformamdie (1 mL). Add, by dropwise addition, asolution of 3-(2-benzylphenacyl)amino!-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole(430 mg, 0.76 mmol) in dimethylformamide (2 mL). Stir at roomtemperature for 15 minutes. Add methyl iodide (49.5 uL, 0.8 mmol) andstir for 2 hours. Quench with water, extract into ethyl acetate, washwith water and dry. Evaporate the solvent in vacuo and purify by flashchromatography (25% ethyl acetate/hexane) to give the title compound.

Anal. Calcd for C₃₁ H₂₈ Cl₂ N₂ O₅ : C, 64.25; H, 4.87; N, 4.83; Found:C, 63.95; H, 5.26; N, 4.86.

Scheme I, step f: 3-(2-Benzylphenacyl)methylamino!-2-carbethoxy-4,6-dichloroindole

Dissolve 3-(2-benzylphenacyl)methylamino!-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole(320 mg, 0.55 mmol) in methylene chloride (5 mL). Add trifluoroaceticacid (1 mL) and stir at room temperature for 3 hours. Evaporate thesolvent in vacuo and recrystallize (ethyl acetate/hexane) to give thetitle compound (250 mg, 95%); mp 208°-209° C.

EXAMPLE 23

Preparation of 3-(2-Benzylphenacyl)methylamino!-2-carboxy-4,6-dichloroindole ##STR48##

Dissolve 3-(2-benzylphenacyl)methylamino!-2-carbethoxy-4,6-dichloroindole (200 mg,0.41 mmol) in tetrahydrofuran (3 mL) and add water (3 mL). Add lithiumhydroxide monohydrate (1.2 mmol) and heat at 60° C. overnight. Addaddition lithium hydroxide monohydrate (1.2 mmol) and heat at 60° C. for5 hours. Allow some of the tetrahydrofuran to evaporate and add methanolto form a homogeneous solution. Heat for 3 days, adding additionallithium hydroxide monohydrate (2.4 mmol). Dilute with water and filter.Acidify, extract into ethyl acetate and dry (MgSO₄). Evaporate thesolvent in vacuo and recrystallize (ethyl acetate/hexane) to give thetitle compound as a white powder (180 mg, 97%); mp 280°-83° C.

Anal. Calcd for C₂₄ H₁₈ Cl₂ N₂ O₃. 0.33 ethyl acetate: C, 63.04; H,4.31; N, 5.81; Found: C, 62.76; H, 4.41; N, 5.65.

EXAMPLE 24

Preparation of 3- (3-Pyridacyl)amino!-2-carbethoxy-4,6-dichloroindole##STR49##

Mix 3-amino-2-carbethoxy-4,6-dichloroindole (7 g, 25.6 mmol), nicotinylchloride hydrochloride (5 g, 28 mmol), dimethylaminopyridine (200 mg)and pyridine (70 mL) and stir for 2 days at room temperature. Pour intowater, filter the white solid and recrystallize (ethyl acetate/methanol)to give the title compound (5.65 g, 58%); mp 247°-48° C.

EXAMPLE 25

Preparation of 3- 3-Pyridacyl)amino!-2-carboxy-4,6-dichloroindole##STR50##

Mix 3- (pyridacyl)amino!-2-carbethoxy-4,6-dichloroindole (390 mg, 1.03mmol), lithium hydroxide monohydrate (3 mmol), tetrahydrofuran (10 mL)and water (10 mL). Stir overnight at room temperature. Dilute with ethylacetate and water, separate the aqueous phase and acidify to pH 3.Filter the precipitate and dry under vacuum to give the title compound;mp 285°-90° C. (dec).

EXAMPLE 26

Preparation of 3-(3-Pyridacyl)methylamino!-2-carbethoxy-4,6-dichloroindole ##STR51##Scheme I, step d₂ : 3-(Pyridacyl)amino!-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole

Suspend 3- (pyridacyl)amino!-2-carbethoxy-2,6-dichloroindole (5.67 g, 15mmol) in tetrahydrofuran (150 mL). Add di-tert-butyl dicarbonate (3.5 g,16 mmol) and dimethylaminopyridine (85 mg, 0.8 mmol). Stir at roomtemperature for 3 hours. Evaporate the solvent in vacuo to a volume of50 mL and dilute with ethyl acetate (100 mL) and hexane (150 mL). Filterto give the title compound; first crop (4.9 g, 69%) and second crop (1.4g, 20%).

Scheme I, step e: 3-(Pyridacyl)methylamino!-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole

Suspend sodium hydride (3.4 mmol) in anhydrous tetrahydrofuran (5 mL)and cool to 0° C. Add, by dropwise addition, a solution of 3-(pyridacyl)amino!-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole(1.5 g, 3.1 mmol) in tetrahydrofuran (25 mL). Stir 1/2 hour, then addmethyl iodide (3.4 mmol) and stir at room temperature overnight. Dilutewith ethyl acetate and water, separate the organic phase and dry(MgSO₄). Evaporate the solvent in vacuo and purify by flashchromatography (50% ethyl acetate/hexane) to give the title compound(1.4 g, 91%).

Scheme I, step f: 3-(Pyridacyl)methylamino!-2-carbethoxy-4,6-dichloroindole

Mix 3-(pyridacyl)methylamino!-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole(1.2 g, 2.44 mmol), trifluroracetic acid (3 mL) and methylene chloride(3 mL). Stir at room temperature for several hours. Evaporate thesolvent in vacuo, dissolve in ethyl acetate, wash with saturated sodiumhydrogen carbonate and saturated sodium chloride. Separate the organicphase and dry (MgSO₄). Evaporate the solvent in vacuo and purify byflash chromatography (50% ethyl acetate/hexane) then recrystallize(ether/hexane) to give the title compound (740 mg, 77%).

EXAMPLE 27

Preparation of 3- (3-Pyridacyl)methylamino!-2-carboxy-4,6-dichloroindole##STR52##

Dissolve 3- (pyridacyl)methylamino!-2-carbethoxy-4,6-dichloroindole (740mg, 1.9 mmol) in tetrahydrofuran (5 mL) and dilute with water (5 mL).Add lithium hydroxide monohydrate (239 mg, 45.7 mmol) and stir overnightat room temperature. Warm to 50° C. for 2 hours, dilute with water/ethylacetate and separate the aqueous phase. Acidify to pH 6 and filter theprecipitate. Dry at 70° C. under vacuum for 48 hours to give the titlecompound as a white powder (611 mg, 88%).

EXAMPLE 28

Preparation of 3-(3-Pyridacyl)methylamino!-2-sodium-carboxylate-4,6-dichloroindole##STR53##

Suspend 3- (3-pyridacyl)methylamino!-2-carboxy-4,6-dichloroindole (110mg, 0.3 mmol) in water (10 mL) and add sodium hydroxide (1.2 mL of a0.25M solution). Warm until a solution was obtained. Filter andfreeze-dry to give the title compound (120 mg, 97%).

EXAMPLE 28a

Preparation of 3-(p-fluorophenacyl)amino!-2-carbethoxy-4,6-dichloroindole ##STR54##

Dissolve 3-amino-2-carbethoxy-4,6-dichloroindole (2.0 g, 7.13 mmol) inmethylene chloride (125 mL) and add p-fluorobenzoyl chloride (0.886 mL,7.5 mmol) followed by triethylamine (1.05 mL, 7.5 mmol). Stir thereaction at room temperature overnight. Add an additional amount ofp-fluorobenzoyl chloride (0.20 mL) and triethylamine (.20 mL) and stirfor 6 hours. Dilute the reaction with ethyl acetate, wash with 1N HCl,saturated sodium bicarbonate, saturated sodium chloride, dry overmagnesium sulfate, filter and concentrate, in vacuo to give a solid.Dissolve the solid in hot ethyl acetate (250 mL), reduce to 200 mL andadd hot hexane (50 mL). Cool the solution and collect to resulting solidto yield the title compound as fluffy white crystals (1.52 g, 53%);241°-243° C.

Anal. Calcd for C₁₈ H₁₃ Cl₂ FN₂ O₃ : C, 54.70; H, 3.31; N, 7.09; Found:C, 54.63; H, 3.39; N, 6.98.

EXAMPLE 28b

Preparation of 3- (p-fluorophenacyl)amino!-2-carboxy-4,6-dichloroindole##STR55##

Mix 3- (p-fluorophenacyl)amino!-2-carbethoxy-4,6-dichloroindole (600 mg,1.52 mmol), lithium hydroxide (191 mg, 4.55 mmol), tetrahydrofuran (20mL) and water (20 mL). Stir overnight at room temperature. Dilute withwater (20 mL) and ethyl acetate (40 mL). Acidify with 1N HCl whilestirring and separate the layers. Dry the organic phase over magnesiumsulfate, filter and concentrate in vacuo. Recrystallize the residue(ethyl acetate/hexane) to yield the title compound as a white powder(440 mg, 79%); mp 259°-261° C.

EXAMPLE 28c

Preparation of 3-(p-fluorophenacyl)methylamino!-2-carbethoxy-4,6-dichloroindole ##STR56##Scheme I step d₂ : 3-(p-fluorophenacyl)amino!-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole

Mix 3- (p-fluorophenacyl)amino!-2-carbethoxy-4,6-dichloroindole (1.5 g,3.8 mmol), di-tert-butyl dicarbonate (890 mg, 4 mmol), tetrahydrofuran(50 mL), dimethylaminopyridine (42 mg, 0.4 mmol) and stir at roomtemperture for 1 hour. Concentrate the reaction in vacuo and purify byflash chromatograpy (25% ethyl actetate/hexane) to yield the titlecompound as a clear oil (1.8 g, 95%).

Scheme I step e: 3-(p-fluorophenacyl)methylamino!-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole

Suspend sodium hydride (132 mg of a 60% dispersion, 3.3 mmol) inanhydrous tetrahydrofuran (10 mL) and cool to 0° C. under a nitrogenatmosphere. Add 3-(p-fluorophenacyl)amino!-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole(1.5 g, 3.0 mmol) in tetrahydrofuran (10 mL) dropwise to the suspension.Stir at 0° C. for 30 minutes. Add methyl iodide (0.205 mL, 3.3 mmol) andstir for 30 minutes at 0° C. Warm the reaction to room temperature andquench with water. Extract with ethyl acetate, dry the organic phaseover magnesium sulfate, filter and concentrate in vacuo. Purify theresidue by flash chromatography (25% ethyl acetate/hexane) to yield thetitle compound (1.3 g, 85%).

Scheme I, step f: 3-(p-fluorophenacyl)methylamino!-2-carbethoxy-4,6-dichloroindole

Dissolve 3-(p-fluorophenacyl)methylamino!-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole(1.2 g, 2.35 mmol) in methylene chloride. Add trifluoracetic acid andstir for 2 hours. Concentrate the reaction in vacuo and recrystallizethe residue from hot ethyl acetate/hexane to yield the title compound(720 mg, 74%).

EXAMPLE 28d

Preparation of 3-(p-fluorophenacyl)methylamino!-2-carboxy-4,6-dichloroindole ##STR57##

Dissolve 3-(p-fluorophenacyl)methylamino!-2-carbethoxy-4,6-dichloroindole (660 mg,1.61 mmol) in tetrahydrofuran (5 mL) and water (5 mL). Add lithiumhydroxide (203 mg, 4.8 mmol) and stir for 24 hours at room temperture.Dilute the reaction with water (20 mL) and ethyl acetate (50 mL) andacidify. Separate the layers and dry the organic phase over magnesiumsulfate, filter and dilute the filtrate with hexane (100 mL).Recrystallize from this solution to yield the title compound as a whitepowder (550 mg, 90%).

Anal. Calcd for C₁₇ H₁₁ Cl₂ FN₂ O₃ : C, 53.56; H, 2.91; N, 7.35; Found:C, 53.46; H, 2.90; N, 7.10.

EXAMPLE 28e

Preparation of 3-(o-fluorophenacyl)amino!-2-carbethoxy-4,6-dichloroindole ##STR58##

Dissolve 3-amino-2-carbethoxy-4,6-dichloroindole (1.09 g, 4 mmol) inmethylene chloride (25 mL) and add triethylamine (0.578 mL, 4 mmol)followed by o-fluorobenzoyl cholride (1 g, 4 mmol). Stir the reactionfor 1 hour at room temperature. Add an additional amount of methylenechloride (25 mL) and stir overnight. Dilute the reaction with ethylacetate (100 mL), wash with water (100 mL) and dry the organic phase.Concentrate in vacuo and recrystallize the residue from ethylacetate/hexane to yield the title compound (1.05 g, 67%); mp >290° C.

Anal. Calcd for C₁₈ H₁₃ Cl₂ FN₂ O₃ : C, 54.70; H, 3.31; N, 7.09; Found:C, 54.77; H, 3.45; N, 6.79.

EXAMPLE 28f

Preparation of 3-(o-fluorophenacyl)methylamino!-2-carbethoxy-4,6-dichloroindole ##STR59##Scheme I, step d₂ :3-(o-fluorophenacyl)amino!-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole

Mix 3- (o-fluorophenacyl)amino!-2-carbethoxy-4,6-dichloroindole (850 mg,2.15 mmol), di-tert-butyl dicarbonate (479 mg, 2.5 mmol),tetrahydrofuran (20 mL), dimethylaminopyridine (42 mg, 0.3 mmol) andstir at room temperture for 15 minutes. Dilute with ethyl acetate (100mL), wash with water, saturated sodium chloride, dry orver magnesiumsulfate, filter and concentrate in vacuo. Recrystallize the residue fromhot hexane containing some diethyl ether to yield the title compound(880 mg, 84%) as colorless crystals.

Anal. Calcd for C₂₃ H₂₁ Cl₂ FN₂ O₅ : C, 55.77; H, 4.27; N, 5.65; Found:C, 55.76; H, 4.47; N, 5.56.

Scheme I, step e: 3-(o-fluorophenacyl)methylamino!-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole

Suspend sodium hydride (80 mg of a 60% dispersion, 2.0 mmol) inanhydrous tetrahydrofuran/dimethylformamide (5 mL/2:1) and cool to 0° C.under a nitrogen atmosphere. Add 3-(p-fluorophenacyl)amino!-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole(880 mg, 1.8 mmol) in tetrahydrofuran/dimethylformamide (20 mL/2:1)dropwise to the suspension. Stir at 0° C. for 30 minutes. Add methyliodide (0.1244 mL, 2.0 mmol) and stir for 30 minutes at 0° C. Warm thereaction to room temperature and after 4 hours quench with water.Extract with ethyl acetate, wash with saturated sodium chloride, dryover magnesium sulfate, filter and concentrate in vacuo to yield thetitle compound.

Scheme I, step f: 3-(o-fluorophenacyl)methylamino!-2-carbethoxy-4,6-dichloroindole

Dissolve 3-(o-fluorophenacyl)methylamino!-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indolefrom above in methylene chloride (5 mL). Add trifluoracetic acid (3 mL)and stir for 5 hours. Concentrate the reaction in vacuo, dilute withethyl acetate (100 mL), wash with saturated sodium carbonate, dry overmagnesium sulfate, filter and concentrate in vacuo. Recrystallize theresidue from ethyl acetate/hexane to yield the title compound (650 mg).

EXAMPLE 28g

Preparation of 3-(o-fluorophenacyl)methylamino!-2-carboxy-4,6-dichloroindole ##STR60##

Mix 3- (o-fluorophenacyl)methylamino!-2-carbethoxy-4,6-dichloroindole(600 mg, 1.47 mmol), lithium hydroxide (184 mg, 4.4 mmol),tetrahydrofuran (10 mL) and water (10 mL). Stir for 24 hours at roomtemperature. Dilute with ethyl acetate (40 mL). Acidify while stirringand separate the layers. Dry the organic phase over magnesium sulfate,filter and concentrate in vacuo. Recrystallize the residue (ethylacetate/hexane) to yield the title compound as a white powder (480 mg,86%).

Anal. Calcd for C₁₇ H₁₁ Cl₂ FN₂ O₃ : C, 53.57; H, 2.91; N, 7.35; Found:C, 53.31; H, 3.05; N, 7.60.

EXAMPLE 28h

Preparation of 3- (m-fluorophenacyl)amino!-2-carbethoxy-4,6-dichloroindole ##STR61##

Dissolve 3-amino-2-carbethoxy-4,6-dichloroindole (1.09 g, 4 mmol) inmethylene chloride (25 mL) and add triethylamine (0.578 mL, 4 mmol)followed by m-fluorobenzoyl chloride (0.488 mL, 4 mmol). Stir thereaction for 1 hour at room temperature. Add an additional amount ofmethylene chloride (25 mL) and stir overnight. Dilute the reaction withethyl acetate (100 mL), wash with water (100 mL) and dry the organicphase. Concentrate in vacuo and recrystallize the residue from ethylacetate/hexane to yield the title compound (1.28 g, 81%); mp 234°-235°C.

Anal. Calcd for C₁₈ H₁₃ Cl₂ FN₂ O₃ : C, 54.70; H, 3.31; N, 7.09; Found:C, 54.58; H, 3.59; N, 7.02.

EXAMPLE 28i

Preparation of 3-(m-fluorophenacyl)methylamino!-2-carbethoxy-4,6-dichloroindole ##STR62##Scheme I, step d₂ : 3-(m-fluorophenacyl)amino!-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole

Mix 3- (m-fluorophenacyl)amino!-2-carbethoxy-4,6-dichloroindole (1.0 g,2.53 mmol), di-tert-butyl dicarbonate (588 mg, 2.7 mmol),tetrahydrofuran (25 mL), dimethylaminopyridine (42 mg, 0.3 mmol) andstir at room temperture for 15 minutes. Dilute with ethyl acetate (100mL), wash with water, saturated sodium chloride, dry orver magnesiumsulfate, filter and concentrate in vacuo. Recrystallize the residue fromhot hexane containing some diethyl ether to yield the title compound(1.1 g, 88%) as colorless crystals.

Anal. Calcd for C₂₃ H₂₁ Cl₂ FN₂ O₅ : C, 55.77; H, 4.27; N, 5.65; Found:C, 55.74; H, 4.56; N, 5.55.

Scheme I, step e: 3-(m-fluorophenacyl)methylamino!-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole

Suspend sodium hydride (97 mg of a 60% dispersion, 2.42 mmol) inanhydrous tetrahydrofuran/dimethylformamide (5 mL/2:1) and cool to 0° C.under a nitrogen atmosphere. Add 3-(m-fluorophenacyl)amino!-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole(1.1 g, 2.22 mmol) in tetrahydrofuran/dimethylformamide (20 mL/2:1)dropwise to the suspension. Stir at 0° C. for 30 minutes. Add methyliodide (0.15 mL, 2.42 mmol) and stir for 30 minutes at 0° C. Warm thereaction to room temperature and after 4 hours quench with water.Extract with ethyl acetate, wash with saturated sodium chloride, dryover magnesium sulfate, filter and concentrate in vacuo to yield thetitle compound.

Scheme I, step f: 3-(m-fluorophenacyl)methylamino!-2-carbethoxy-4,6-dichloroindole

Dissolve 3-(m-fluorophenacyl)methylamino!-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indolefrom above in methylene chloride (5 mL). Add trifluoracetic acid (3 mL)and stir for 5 hours. Concentrate the reaction in vacuo, dilute withethyl acetate (100 mL), wash with saturated sodium carbonate, dry overmagnesium sulfate, filter and concentrate in vacuo. Recrystallize theresidue from ethyl acetate/hexane to yield the title compound (760 mg).

EXAMPLE 28j

Preparation of 3-(m-fluorophenacyl)methylamino!-2-carboxy-4,6-dichloroindole ##STR63##

Mix 3- (m-fluorophenacyl)methylamino!-2-carbethoxy-4,6-dichloroindole(700 mg, 1.7 mmol), lithium hydroxide (210 mg, 5 mmol), tetrahydrofuran(10 mL) and water (10 mL). Stir for hours at room temperature. Dilutewith ethyl acetate (40 mL). Acidify while stirring and separate thelayers. Dry the organic phase over magnesium sulfate, filter andconcentrate in vacuo. Recrystallize the residue (ethyl acetate/hexane)to yield the title compound as a white powder (590 mg, 91%); mp270°-280° C.

Anal. Calcd for C₁₇ H₁₁ Cl₂ FN₂ O₃ : C, 53.57; H, 2.91; N, 7.35; Found:C, 53.54; H, 3.15; N, 7.24.

EXAMPLE 28k

Preparation of 3-(p-trifluoromethylphenacyl)amino!-2-carbethoxy-4,6-dichloroindole##STR64##

Dissolve 3-amino-2-carbethoxy-4,6-dichloroindole (1.09 g, 4 mmol) inmethylene chloride (25 mL) and add triethylamine (0.578 mL, 4 mmol)followed by p-trifluoromethylbenzoyl chloride (0.488 mL, 4 mmol). Stirthe reaction for 1 hour at room temperature. Add an additional amount ofmethylene chloride (25 mL) and stir overnight. Dilute the reaction withethyl acetate (100 mL), wash with water (100 mL) and dry the organicphase. Concentrate in vacuo and recrystallize the residue from ethylacetate/hexane to yield the title compound as a white fluffy solid (1.42g, 80%); mp 250°-252° C.

Anal. Calcd for C₁₉ H₁₃ Cl₂ F₃ N₂ O₃ : C, 51.26; H, 2.94; N, 6.29;Found: C, 51.51; H, 3.17; N, 6.59.

EXAMPLE 28l

Preparation of 3-(p-trifluoromethylphenacyl)methylamino!-2-carbethoxy-4,6-dichloroindole##STR65## Scheme I, step d₂ : 3-(p-trifluoromethylphenacyl)amino!-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole

Mix 3- (p-trifluoromethylphenacyl)amino!-2-carbethoxy-4,6-dichloroindole(1.18 g, 2.6 mmol), di-tert-butyl dicarbonate (610 mg, 2.8 mmol),tetrahydrofuran (25 mL), dimethylaminopyridine (42 mg, 0.3 mmol) andstir at room temperture for 15 minutes. Dilute with ethyl acetate (100mL), wash with water, saturated sodium chloride, dry over magnesiumsulfate, filter and concentrate in vacuo. Recrystallize the residue fromhot hexane containing some diethyl ether to yield the title compound(1.1 g, 77%) as colorless crystals; mp 159°-160° C.

Anal. Calcd for C₂₄ H₂₁ Cl₂ F₃ N₂ O₅ : C, 52.86; H, 3.88; N, 5.14;Found: C, 52.89; H, 4.11; N, 5.39.

Scheme I, step e: 3-(p-trifluoromethylphenacyl)methylamino!-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole

Suspend sodium hydride (88 mg of a 60% dispersion, 2.2 mmol) inanhydrous tetrahydrofuran/dimethylformamide (5 mL/2:1) and cool to 0° C.under a nitrogen atmosphere. Add 3-(p-trifluoromethylphenacyl)amino!-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole(1.1 g, 2.0 mmol) in tetrahydrofuran/dimethylformamide (20 mL/2:1)dropwise to the suspension. Stir at 0° C. for 30 minutes. Add methyliodide (0.137 mL, 2.2 mmol) and stir for 30 minutes at 0° C. Warm thereaction to room temperature and after 4 hours quench with water.Extract with ethyl acetate, wash with saturated sodium chloride, dryover magnesium sulfate, filter and concentrate in vacuo to yield thetitle compound.

Scheme I, step f: 3-(p-trifluoromethylphenacyl)methylamino!-2-carbethoxy-4,6-dichloroindole

Dissolve 3-(p-trifluoromethylphenacyl)methylamino!-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indolefrom above in methylene chloride (5 mL). Add trifluoracetic acid (3 mL)and stir for 5 hours. Concentrate the reaction in vacuo, dilute withethyl acetate (100 mL), wash with saturated sodium carbonate, dry overmagnesium sulfate, filter and concentrate in vacuo. Recrystallize theresidue from ethyl acetate/hexane to yield the title compound (820 mg).

EXAMPLE 28m

Preparation of 3-(p-trifluoromethylphenacyl)methylamino!-2-carbethoxy-4,6-dichloroindole##STR66##

Mix 3-(p-trifluoromethylphenacyl)methylamino!-2-carbethoxy-4,6-dichloroindole(750 mg, 1.7 mmol), lithium hydroxide (210 mg, 5 mmol), tetrahydrofuran(10 mL) and water (10 mL). Stir for 24 hours at room temperature. Dilutewith ethyl acetate (40 mL). Acidify while stirring and separate thelayers. Dry the organic phase over magnesium sulfate, filter andconcentrate in vacuo. Recrystallize the residue (ethyl acetate/hexane)to yield the title compound as a white powder (590 mg, 81%); mp232°-234° C.

Anal. Calcd for C₁₈ H₁₁ Cl₂ F₃ N₂ O₃ : C, 50.14; H, 2.57; N, 6.50;Found: C, 49.88; H, 2.61; N, 6.48.

EXAMPLE 28n

Preparation of 3-(p-chlorophenacyl)amino!-2-carbethoxy-4,6-dichloroindole ##STR67##

Dissolve 3-amino-2-carbethoxy-4,6-dichloroindole (2.2 g, 8 mmol) inmethylene chloride (70 mL) and add triethylamine (1.16 mL, 8 mmol)followed by p-chlorobenzoyl chloride (0.976 mL, 8 mmol). Stir thereaction 48 hours at room temperature. Dilute the reaction with ethylacetate (300 mL), wash with water (100 mL), dry the organic phase overmagnesium sulfate, filter and concentrate in vacuo. Recrystallize theresidue from ethyl acetate/hexane to yield the title compound as afluffy solid (2.7 g, 79%).

EXAMPLE 28p

Preparation of 3-(p-chlorophenacyl)methylamino!-2-carbethoxy-4,6-dichloroindole ##STR68##Scheme I, step d₂ : 3-(p-chlorophenacyl)amino!-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole

Mix 3- (p-chlorophenacyl)amino!-2-carbethoxy-4,6-dichloroindole (2 g,4.8 mmol), di-tert-butyl dicarbonate (1 g, 4.8 mmol), tetrahydrofuran(90 mL), dimethylaminopyridine (42 mg, 0.3 mmol) and stir at roomtemperture for 1 hour. Dilute with ethyl acetate (100 mL), wash withwater, saturated sodium chloride, dry orver magnesium sulfate, filterand concentrate in vacuo. Recrystallize the residue from ethylacetate/hexane to yield the title compound (2.3 g, 94%).

Scheme I, step e: 3-(p-chlorophenacyl)methylamino!-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole

Suspend sodium hydride (160 mg of a 60% dispersion, 4 mmol) in anhydroustetrahydrofuran/dimethylformamide (3 mL/2:1) and cool to 0° C. under anitrogen atmosphere. Add 3-(p-chlorophenacyl)amino!-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole(2 g, 3.9 mmol) in tetrahydrofuran/dimethylformamide (10 mL/2:1)dropwise to the suspension. Stir at 0° C. for 30 minutes. Add methyliodide (0.137 mL, 2.2 mmol) and stir for 30 minutes at 0° C. Warm thereaction to room temperature and after 4 hours quench with water (20mL). Extract with ethyl acetate (20 mL), wash with saturated sodiumchloride, dry over magnesium sulfate, filter and concentrate in vacuo toyield the title compound.

Scheme I, step f: 3-(p-chlorophenacyl)methylamino!-2-carbethoxy-4,6-dichloroindole

Dissolve 3-(p-chlorophenacyl)methylamino!-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indolefrom above in methylene chloride (15 mL). Add trifluoracetic acid (5 mL)and stir for 5 hours. Concentrate the reaction in vacuo, dilute withethyl acetate (100 mL), wash with saturated sodium carbonate, dry overmagnesium sulfate, filter and concentrate in vacuo. Recrystallize theresidue from ethyl acetate/hexane to yield the title compound (1.3 g).

EXAMPLE 28Q

Preparation of 3-(p-chlorophenacyl)methylamino!-2-carboxy-4,6-dichloroindole ##STR69##

Mix 3- (p-chlorophenacyl)methylamino!-2-carbethoxy-4,6-dichloroindole(1.3 g, 3.1 mmol), excess lithium hydroxide, tetrahydrofuran and waterand stir overnight. Dilute with ethyl acetate and separate the layers.Dry the organic phase over magnesium sulfate, filter and concentrate invacuo to yield the title compound; mp 279°-283° C.

Anal. Calcd for C₁₇ H₁₁ Cl₃ N₂ O₃ : C, 51.35; H, 2.79; N, 7.04; Found:C, 51.30; H, 2.81; N, 7.00.

EXAMPLE 29

Preparation of 3- (Phenylsulfonyl)amino!-2-carbethoxy-4,6-dichloroindole##STR70##

Mix 3-amino-2-carbethoxy-4,6-dichloroindole (3.31 g, 12.1 mmol) andanhydrous pyridine (50 mL). Add, by dropwise addition, phenylsulfonylchloride (2.35 g, 13.33 mmol). Stir for 48 hours at room temperature.Pour into 1N hydrochloric acid (500 mL), extract with ethyl acetate anddry (MgSO₄). Evaporate the solvent in vacuo and recrystallize (ethylacetate/hexane) to give the title compound (3.15 g, 63%); mp 245°-7° C.

EXAMPLE 30

Preparation of 3- (Phenylsulfonyl)amino!-2-carboxy-4,6-dichloroindole##STR71##

Mix 3- (phenylsulfonyl)amino!-2-carbethoxy-4,6-dichloroindole (0.35 g,0.847 mmol), tetrahydrofuran (10 mL) and water (7 mL). Add lithiumhydroxide monohydrate (0.11 g, 2.54 mmol) and stir at room temperatureovernight. Warm at 65° C. for 5 hours, pour into water and acidify to pH1 with 1N hydrochloric acid. Extract into ethyl acetate, dry (MgSO₄) andevaporate the solvent in vacuo. Recrystallize (ethyl acetate/hexane) togive the title compound (0.2 g, 61%); mp 229°-35° C. (dec).

EXAMPLE 31

Preparation of 3-(Phenylsulfonyl)methylamino!-2-carbethoxy-4,6-dichloroindole ##STR72##Scheme I, step d₂ : 3-(Phenylsulfonyl)amino!-2-carbethoxy-4,6-dichloro-tert-butyloxycarbonyl-indole

Dissolve 3- (phenylsulfonyl)amino!-2-carbethoxy-4,6-dichloroindole (5.0g, 12.10 mmol) in anhydrous tetrahydrofuran (200ml) and adddi-tert-butyldicarbonate (2.91 g, 13.31 mmol), followed bydimethylaminopyridine (0.15 g, 1.21 mmol). Stir at room temperature for24 hours, pour into 1N hydrochloric acid (200 mL) and extract into ethylacetate. Wash with saturated sodium chloride, dry (MgSO₄) and evaporatethe solvent in vacuo to give 6.34 g crude product. Recrystallize (ethylacetate/hexane) to give the title compound.

Scheme I, step e: 3-(Phenylsulfonyl)methylamino!-2-carbethoxy-4,6-dichloro-tert-butyloxycarbonyl-indole

Mix 3-(phenylsulfonyl)amino!-2-carbethoxy-4,6-dichloro-tert-butyloxycarbonyl-indole(0.77 g, 1.5 mmol), methanol (52.9 mg, 1.65 mmol), triphenylphosphine(434 mg, 1.65 mmol) and anhydrous tetrahydrofuran (10 mL). Add, bydropwise addition, a solution of diethyl azodicarboxylate (288 mg, 1.65mmol) in anhydrous tetrahydrofuran (10 mL). Stir at room temperature for5 hours. Evaporate the solvent in vacuo and purify by flashchromatography (10% ethyl acetate/hexane) to give the title compound(490 mg, 62%).

Scheme I, step f: 3-(Phenylsulfonyl)methylamino!-2-carbethoxy-4,6-dichloroindole

Dissolve 3-(phenylsulfonyl)methylamino!-2-carbethoxy-4,6-dichloro-tert-butyloxycarbonyl-indole(400 mg, 0.758 mmol) in methylene chloride (15 mL). Add, by dropwiseaddition, trifluoroacetic acid (15 mL) and stir at room temperature for3 hours. Evaporate the solvent in vacuo and treat the resulting residuewith saturated sodium hydrogen carbonate. Extact into methylene chlorideand dry (MgSO₄). Recrystallize (ethyl acetate/hexane) to give the titlecompound (70 mg, 22%); mp 244°-45° C.

EXAMPLE 32

Preparation of 3-(Phenylsulfonyl)methylamino!-2-carboxy-4,6-dichloroindole ##STR73##

Mix 3- (phenylsulfonyl)methylamino!-2-carbethoxy-4,6-dichloroindole (185mg, 0.433 mmol), tetrahydrofuran (25 mL) and water (25 mL). Add lithiumhydroxide monohydrate (2.6 mmol) and stir at room temperature for 3days, then at reflux for 5 hours. Pour into 1N hydrochloric acid (200mL) and extract into ethyl acetate. Dry (MgSO₄) and evaporate thesolvent in vacuo. Recrystallize (ethyl acetate/hexane) to give the titlecompound (122 mg, 71%); mp 286°-90° C.

EXAMPLE 33

Preparation of 3-(Methyloxalylate)amino!-2-carbethoxy-4,6-dichloroindole ##STR74##

Mix 3-amino-2-carbethoxy-4,6-dichloroindole (3.8 g, 13.91 mmol),triethylamine (1.55 g, 15.3 mmol) and methylene chloride (250 mL). Addmethyl oxalylchloride (1.88 g, 15.30 mmol) at stir at room temperaturefor 3.5 hours. Pour into saturated sodium hydrogen carbonate andseparate the organic phase. Wash with saturated sodium chloride, dry(MgSO₄) and evaporate the solvent in vacuo to give a tan solid.Recrystallize (ethyl acetate/hexane) to give the title compound (3.47 g,69%); mp 192°-3° C.

EXAMPLE 34

Preparation of 3- (Oxalyl)amino!-2-carboxy-4,6-dichloroindole ##STR75##

Dissolve 3- (methyloxalylate)amino!-2-carbethoxy-4,6-dichloroindole (180mg, 0.5 mmol) in tetrahydrofuran (2.5 mL) and water (2.5 mL). Addlithium hydroxide monohydrate (1.5 mmol) and stir overnight at roomtemperature. Dilute with water and wash with ethyl acetate. Acidify with6N hydrochloric acid and extract with ethyl acetate. Dry (MgSO₄) andevaporate the solvent in vacuo. Recrystallize (ethyl acetate/hexane) togive the title compound (70 mg, 45%).

EXAMPLE 35

Preparation of 3-(Methyloxalylate)benzylamino!-2-carbethoxy-4,6-dichloroindole ##STR76##Scheme I, step d₂ : 3-(Methyloxalylate)amino!-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole

Dissolve 3- (methyloxalylate)amino!-2-carbethoxy-4,6-dichloroindole(2.04 g, 5.70 mmol) in tetrahydrofuran (40 mL) and add di-tert-butyldicarbonate (1.37 g, 6.27 mmol) and dimethylaminopyridine (catalytic).Stir at room temperature for 24 hours and evaporate the solvent invacuo. Purify by flash chromatography (2:1 hexane/ethyl acetate) to give1.51 g crude product. Recrystallize (ethyl acetate/hexane) to give thetitle compound (1.28 g, 49%).

Scheme I, step e: 3-(Methyloxalylate)benzylamino!-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole

Suspend sodium hydride (47.9 mg of a 60% dispersion, 1.20 mmol) indimethylformamide (10 mL), cool to 0° C. and place under an inertatmosphere. Add a solution of 3-(methyloxalylate)amino!-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole(500 mg, 1.09 mmol) in dimethylformamide (15 mL). Stir for 20 minutes,remove the ice bath and stir for an additional 15 minutes. Add benzylbromide (205 mg, 1.20 mmol) and stir for 3 hours. Pour onto 1Nhydrochloric acid and extract with ethyl ether. Dry and evaporate thesolvent in vacuo to give a white solid. Recrystallize (ethylacetate/hexane) to give the title compound (426 mg, 72%).

Scheme I, step f: 3- (Methyloxalylate)benzylamino!-2-carbethoxy4,6-dichloroindole

Dissolve 3-(methyloxalylate)benzylamino!-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole(351 mg, 0.586 mmol) in methylene chloride (15 mL) and addtrifluroracetic acid (15 mL). Stir for 24 hours and pour into saturatedsodium hydrogen carbonate (100 mL). Extract into methylene chloride,wash with water, dry (MgSO₄) and evaporate the solvent in vacuo.Recrystallize (ethyl acetate/hexane) to give the title compound as whitecrystals (70 mg, 27%); mp 183°-85° C.

EXAMPLE 36

Preparation of 3- (Oxalyl)benzylamino!-2-carboxy-4,6-dichloroindole##STR77##

Mix 3- (methyloxalylate)benzylamino!-2-carbethoxy 4,6-dichloroindole(180 mg, 0.401 mmol), tetrahydrofuran (12.5 mL) and water (12.5 mL). Addlithium hydroxide monohydrate (67 mg, 1.6 mmol) and stir at roomtemperature for 48 hours. Pour into 1N hydrochloric acid (100 mL) andextract with ethyl acetate. Dry (MgSO₄) and evaporate the solvent invacuo. Recrystallize (ethyl acetate/hexane) to give the title compoundas a white solid (126 mg, 77%); mp 228°-32° C. (dec).

EXAMPLE 37

Preparation of 3-(Methyloxalylate)methylamino!-2-carbethoxy-4,6-dichloroindole ##STR78##Scheme I, step e: 3-(Methyloxalylate)methylamino!-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole

Suspend sodium hydride (47.96 mg of a 60% dispersion, 1.20 mmol) indimethylformamide (20 mL), cool to 0° C. and place under nitrogenatmosphere. Add, by dropwise addition, a solution of 3-(methyloxalylate)amino!-2-carbethoxy-4,6-dichloro-tert-butyloxycarbonyl-indole(500 mg, 1.09 mmol) in dimethylformamide (30 mL). Allow to warm to roomtemperature and stir for 30 minutes. Add methyl iodide (170 mg) and stirovernight. Pour onto 1N hydrochloric acid and extract with ethyl ether.Dry and evaporate the solvent in vacuo. Recrystallize (ethylacetate/hexane) to give the title compound.

Scheme I, step f: 3-(Methyloxalylate)methylamino!-2-carbethoxy-4,6-dichloroindole

Dissolve 3-(methyloxalylate)methylamino!-2-carbethoxy-4,6-dichloro-1-tert-butyloxycarbonyl-indole(430 mg, 0.909 mmol) in methylene chloride (15 mL). Add trifluoroaceticacid (20 mL) and stir for 24 hours. Evaporate the solvent in vacuo andtreat the resulting residue with saturated sodium hydrogen carbonate.Extact into methylene chloride and dry (MgSO₄). Evaporate the solvent invacuo and recrystallize (ethyl acetate/hexane) to give the titlecompound (221 mg, 65%).

EXAMPLE 38

Preparation of 3- (Oxalyl)methylamino!-2-carboxy-4,6-dichloroindole##STR79##

Mix 3- (methyloxalylate)methylamino!-2-carbethoxy-4,6-dichloroindole(156 mg, 0.418 mmol) in tetrahydrofuran (25 mL) and water (25 mL). Addlithium hydroxide monohydrate (88 mg, 2.09 mmol) and stir for 24 hours.Pour into 1N hydrochloride acid and extract into ethyl acetate. Washwith water, dry (MgSO₄) and evaporate the solvent in vacuo.Recrystallize (ethyl acetate/hexane) to give the title compound as awhite solid (114 mg, 83%); mp 230°-34° C. (dec).

EXAMPLE 39

Preparation of 3-(4-Nitrophenacyl)amino!-2-carbethoxy-4,6-dichloroindole ##STR80##

Dissolve 3-amino-2-carbethoxy-4,6-dichloroindole (10 g, 36.6 mmol) inanhydrous pyridine (100 mL). Add 4-nitrobenzoyl chloride (7.47 g, 40.27mmol) and stir for 5 hours. Pour into 1N hydrochloric acid (500 mL) andextract into ethyl acetate. Evaporate the solvent in vacuo and dry at70° C. under vacuum to give the title compound (15.75 g, 100%); mp283°-86° C.

EXAMPLE 40

Preparation of 3- (4-Nitrophenacyl)amino!-2-carboxy-4,6-dichloroindole##STR81##

Mix 3- (4-nitrophenacyl)amino!-2-carbethoxy-4,6-dichloroindole (161 mg,0.381 mmol), tetrahydrofuran (20 ml) and water (20 mL). Add lithiumhydroxide monohydrate (64 mg, 1.52 mmol) and stir overnight. Heat atreflux for 4 hours, cool to room temperature and pour onto 1Nhydrochloric acid (100 mL). Collect the resulting solid by filtrationand air dry to give the title compound (148 mg, 99%); mp 270°-72° C.

EXAMPLE 41

Preparation of 3-(4-Aminophenacyl)amino!-2-carbethoxy-4,6-dichloroindole ##STR82##

Dissolve 3- (4-nitrophenacyl)amino!-2-carbethoxy-4,6-dichloroindole (0.5g, 1.184 mmol) in ethanol (20 mL) and add tin (II) chloride monohydrate(1.60 g, 7.1 mmol). Heat to 70° C. overnight. Pour into ethylacetate/water (200 mL) and add solid sodium hydrogen carbonate to obtainpH 7. Filter and evaporate the solvent in vacuo to give the titlecompound as a pale yellow oil (0.477, 100%).

EXAMPLE 41a

Preparation of 3- (phenacyl)amino!-2-carbethoxy-5,6-dichloroindole##STR83## Scheme IV, step a, Preparation of starting material:3-Nitro-2-carbethoxy-5,6-dichloroindole

Dissolve 3,4-dichlorophenylhydrazine hydrochloride (300 g) in anhydrousethanol (2 L). Add ethyl pyruvate (153.6 mL) and concentrated sulfuricacid (25 mL). Sir at room temperature under a nitrogen atmosphere for 3hours. Evaporate the solvent in vacuo, take up the residue in ethylacetate/water and treat with saturated sodium hydrogen carbonate.Separate the aqueous phase and extract with ethyl acetate. Combine theorganic phases, dry (MgSO₄) and evaporate the solvent in vacuo to givethe 3,4-dichlorophenylhydrazone of ethyl pyruvate and as a solid. Both Eand Z isomers are obtained.

Add polyphosphoric acid (2 kg) to the 3,4-dichlorophenylhydrazone ofethyl pyruvate (100 g) and heat on a steam bath for 5 hours. Add a smallamount of ice and pour onto ice to decompose the polyphosphoric acid.Extract the resulting suspension into ethyl acetate (3×1 L) and dry(MgSO₄). Evaporate the solvent in vacuo to give a light brown solid.Stir the solid with ethyl ether (1 L) for 1 hour and filter off2-carboxyethyl-4,6-dichloroindole. Heat the filtrate with activatedcharcoal, filter through diatomaceous earth and evaporate the solvent invacuo to give a second crop of 2-carboxyethyl-4,5-dichloroindole as atan solid (89.4 g total, 95%).

Mix 2-carboxyethyl-5,6-dichloroindole (50 g) and acetic acid (1 L) andadd, by dropwise addition, 90% (white fuming) nitric acid (250 mL).Apply a water bath as necessary to keep the temperature below 29° C.Stir for 10 minutes after all of the solid is dissolved and pour intoice (6 L). Filter off the solid and wash with water. Dissolve the solidin ethyl acetate, treat with saturated sodium hydrogen carbonatesolution, and separate the organic phase. Dry (MgSO₄), filter andevaporate the solvent in vacuo to give the crude product as a tan solid.Slurry the solid in a small amount of chloroform, filter and dry to givethe title compound.

Scheme IV, step b: 3-Amino-2-carbethoxy-5,6-dichloroindole

Dissolve 3-nitro-2-carbethoxy-5,6-dichloroindole (38.1 g) in ethanol (1L) and add tin (II) chloride dihydrate (163 g). Warm to between 65° and75° C. for 4 to 5 hours. Cool to room temperature and pour into amixture of ethyl acetate (3 L) and water (2 L). Add solid potassiumcarbonate and stir occasionally until the carbon dioxide evolutionceases. Filter throught diatomaceous earth and separate the organicphase of the filtrate. Dry (MgSO₄) and evaporate the solvent in vacuo togive the title compound.

Scheme I, step c: 3- (phenacyl)amino!-2-carbethoxy-5,6-dichloroindole

Dissolve 3-amino-2-carbethoxy-5,6-dichloroindole (2.2 g, 8 mmol) inmethylene chloride (70 mL) and add triethylamine (1.16 mL, 8 mmol)followed by benzoyl chloride (0.93 mL, 8 mmol). Stir the reaction 48hours at room temperature. Dilute the reaction with ethyl acetate (300mL), wash with water (100 mL), dry the organic phase over magnesiumsulfate, filter and concentrate in vacuo. Recrystallize the residue fromethyl acetate/hexane to yield the title compound.

EXAMPLE 41b

Preparation of 3- (phenacyl)methylamino!-2-carbethoxy-5,6-dichloroindole##STR84## Scheme I, step d₂ : 3-(phenacyl)amino!-2-carbethoxy-5,6-dichloro-1-(tert-butyloxycarbonyl)-indole

Mix 3- (phenacyl)amino!-2-carbethoxy-5,6-dichloroindole (2 g, 4.8 mmol),di-tert-butyl dicarbonate (1 g, 4.8 mmol), tetrahydrofuran (90 mL),dimethylaminopyridine (42 mg, 0.3 mmol) and stir at room temperture for1 hour. Dilute with ethyl acetate (100 mL), wash with water, saturatedsodium chloride, dry orver magnesium sulfate, filter and concentrate invacuo. Recrystallize the residue from ethyl acetate/hexane to yield thetitle compound.

Scheme I, step e: 3-(phenacyl)methylamino!-2-carbethoxy-5,6-dichloro-1-(tert-butyloxycarbonyl)-indole

Suspend sodium hydride (160 mg of a 60% dispersion, 4 mmol) in anhydroustetrahydrofuran/dimethylformamide (3 mL/2:1) and cool to 0° C. under anitrogen atmosphere. Add 3-(phenacyl)amino!-2-carbethoxy-5,6-dichloro-1-(tert-butyloxycarbonyl)-indole(2 g, 3.9 mmol) in tetrahydrofuran/dimethylformamide (10 mL/2:1)dropwise to the suspension. Stir at 0° C. for 30 minutes. Add methyliodide (0.137 mL, 2.2 mmol) and stir for 30 minutes at 0° C. Warm thereaction to room temperature and after 4 hours quench with water (20mL). Extract with ethyl acetate (20 mL), wash with saturated sodiumchloride, dry over magnesium sulfate, filter and concentrate in vacuo toyield the title compound.

Scheme I, step f: 3-(phenacyl)methylamino!-2-carbethoxy-5,6-dichloroindole

Dissolve 3-(phenacyl)methylamino!-2-carbethoxy-5,6-dichloro-1-(tert-butyloxycarbonyl)-indolefrom above in methylene chloride (15 mL). Add trifluoracetic acid (5 mL)and stir for 5 hours. Concentrate the reaction in vacuo, dilute withethyl acetate (100 mL), wash with saturated sodium carbonate, dry overmagnesium sulfate, filter and concentrate in vacuo. Recrystallize theresidue from ethyl acetate/hexane to yield the title compound.

EXAMPLE 41c

Preparation of 3- (phenacyl)methylamino!-2-carbethoxy-5,6-dichloroindole##STR85##

Mix 3- (phenacyl)methylamino!-2-carbethoxy-5,6-dichloroindole (750 mg,1.78 mmol), lithium hydroxide (210 mg, 5 mmol), tetrahydrofuran (10 mL)and water (10 mL). Stir for 24 hours at room temperature. Dilute withethyl acetate (40 mL). Acidify while stirring and separate the layers.Dry the organic phase over magnesium sulfate, filter and concentrate invacuo. Recrystallize the residue (ethyl acetate/hexane) to yield thetitle compound.

EXAMPLE 41d

Preparation of 3-(phenacyl)methylamino!-2-carbonylaminotetrazole-6-chloroindole ##STR86##

Scheme IV. Dissolve 3- (phenacyl)methylamino!-2-carboxy-6-chloroindole(1 mmol) in toluene, add thionyl chloride (2 mL) and warm to 50° C. for3 hours. After cooling, concentrate the reaction in vacuo andreconcentrate two more times from toluene. Dissolve the acid chloride inmethylene chloride and treat with 5-aminotetrazole (1 mmol). Stir thereaction for 24 hours. Dilute the reaction with water, extract withethyl acetate, dry the organic phase over magnesium sulfate, filter andconcentrate to yield the title compound.

The compounds of Formulae Ia through Ic are excitatory amino acidantagonists. They antagonize the effects which excitatory amino acidshave upon the NMDA receptor complex. They preferentially bind to thestrychnine-insensitive glycine binding site associated with the NMDAreceptor complex. They are useful in the treatment of a number ofdisease states.

The compounds exhibit anti-convulsant properties and are useful in thetreatment of epilepsy. They are useful in the treatment of grand malseizures, petit mal seizures, psychomotor seizures, autonomic seizures,etc. One method of demonstrating their anti-epileptic properties is bytheir ability to inhibit the seizures that are caused by theadministration of quinolinic acid. This test can be conducted in thefollowing manner.

One group containing ten mice are administered 0.01-100 μg of testcompound intracerebroventricularly in a volume of 5 microliters ofsaline. A second control group containing an equal number of mice areadministered an equal volume of saline as a control. Approximately 5minutes later, both groups are administered 7.7 micrograms of quinolinicacid intracerebroventricularly in a volume of 5 microliters of saline.The animals are observed for 15 minutes thereafter for signs ofclonic-tonic seizures. The control group will have a statisticallyhigher rate of clonic-tonic seizures than will the test group.

Another method of demonstrating the anti-epileptic properties of thesecompounds is by their ability to inhibit audiogenic convulsions in DBA/2mice. This test can be conducted in the following manner. Typically onegroup of from 6-8 male DBA/2J audiogenic susceptible mice areadministered from about 0.01 μg to about 100 μg of the test compound.The test compound is administered intracerebrally into the lateralventricle of the brain. A second group of mice are administered an equalvolume of saline control by the same route. Five minutes later the miceare placed individually in glass jars and are exposed to a soundstimulus of 110 decibels for 30 seconds. Each mouse is observed duringthe sound exposure for signs of seizure activity. The control group willhave a statistically higher incidence of seizures than the group whichreceives the test compound.

The compounds of Formulae Ia through Ic are useful for preventing orminimizing the damage which nervous tissues contained within the CNSsuffer upon exposure to either ischemic, hypoxic, or hypoglycemicconditions or as the result of physical trauma. Representative examplesof such conditions include strokes or cerebrovascular accidents,hyperinsulinemia, cardiac arrest, physical trauma, drownings,suffocation, and neonatal anoxic trauma. The compounds should beadministered to the patient within 24 hours of the onset of the hypoxic,ischemic, or hypoglycemic condition in order for the compounds toeffectively minimize the CNS damage which the patient will experience.

The compounds are also useful in the treatment of neurodegenerativediseases such as Huntington's disease, Alzheimer's disease, seniledementia, glutaric acidaemia type I, Parkinson's disease, multi-infarctdementia, and neuronal damage associated with uncontrolled seizures. Theadministration of these compounds to a patient experiencing such acondition will serve to either prevent the patient from experiencingfurther neurodegeneration or it will decrease the rate at which theneurodegeneration occurs.

As is apparent to those skilled in the art, the compounds will notcorrect any CNS damage that has already occurred as the result of eitherdisease, or a lack of oxygen or sugar. As used in this application, theterm "treat" refers to the ability of the compounds to prevent furtherdamage or delay the rate at which any further damage occurs.

The compounds exhibit an anxiolytic effect and are thus useful in thetreatment of anxiety. These anxiolytic properties can be demonstrated bytheir ability to block distress vocalizations in rat pups. This test isbased upon the phenomenon that when a rat pup is removed from itslitter, it will emit an ultrasonic vocalization. It was discovered thatanxiolytic agents block these vocalizations. The testing methods havebeen described by Gardner, C. R., Distress vocalization in rat pups: asimple screening method for anxiolytic drugs. J. Pharmacol. Methods,14:181-187 (1985) and Insel et al. Rat pup ultrasonic isolation calls:Possible mediation by the benzodiazepine receptor complex. Pharmacol.Biochem. Behav., 24:1263-1267 (1986).

The compounds also exhibit an analgesic effect and are useful incontrolling pain. The compounds are also effective in the treatment ofmigraine.

In order to exhibit these therapeutic properties, the compounds need tobe administered in a quantity sufficient to inhibit the effect which theexcitatory amino acids have upon the NMDA receptor complex. The dosagerange at which these compounds exhibit this antagonistic effect can varywidely depending upon the particular disease being treated, the severityof the patient's disease, the patient, the particular compound beingadministered, the route of administration, and the presence of otherunderlying disease states within the patient, etc. Typically thecompounds exhibit their therapeutic effect at a dosage range of fromabout 0.1 mg/kg/day to about 50 mg/kg/day for any of the diseases orconditions listed above. Repetitive daily administration may bedesirable and will vary according to the conditions outlined above.

The compounds of the present invention may be administered by a varietyof routes. They are effective if administered orally. The compounds mayalso be administered parenterally (i.e. subcutaneously, intravenously,intramuscularly, intraperitoneally, or intrathecally).

Pharmaceutical compositions can be manufactured utilizing techniquesknown in the art. Typically an antagonistic amount of the compound willbe admixed with a pharmaceutically acceptable carrier.

For oral administration, the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, lozenges, melts,powders, suspensions, or emulsions. Solid unit dosage forms can becapsules of the ordinary gelatin type containing, for example,surfactants, lubricants and inert fillers such as lactose, sucrose, andcornstarch or they can be sustained release preparations.

In another embodiment, the compounds of Formula I can be tableted withconventional tablet bases such as lactose, sucrose, and cornstarch incombination with binders, such as acacia, cornstarch, or gelatin,disintegrating agents such as potato starch or alginic acid, and alubricant such as stearic acid or magnesium stearate. Liquidpreparations are prepared by dissolving the active ingredient in anaqueous or non-aqueous pharmaceutically acceptable solvent which mayalso contain suspending agents, sweetening agents, flavoring agents, andpreservative agents as are known in the art.

For parenteral administration the compounds may be dissolved in aphysiologically acceptable pharmaceutical carrier and administered aseither a solution or a suspension. Illustrative of suitablepharmaceutical carriers are water, saline, dextrose solutions, fructosesolutions, ethanol, or oils of animal, vegetative, or synthetic origin.The pharmaceutical carrier may also contain preservatives, buffers,etc., as are known in the art. When the compounds are being administeredintrathecally, they may also be dissolved in cerebrospinal fluid as isknown in the art.

The compounds of this invention can also be administered topically. Thiscan be accomplished by simply preparing a solution of the compound to beadministered, preferably using a solvent known to promote transdermalabsorption such as ethanol or dimethyl sulfoxide (DMSO) with or withoutother excipients. Preferably topical administration will be accomplishedusing a patch either of the reservoir and porous membrane type or of asolid matrix variety.

Some suitable transdermal devices are described in U.S. Pat. Nos.3,742,951, 3,797,494, 3,996,934, and 4,031,894. These devices generallycontain a backing member which defines one of its face surfaces, anactive agent permeable adhesive layer defining the other face surfaceand at least one reservoir containing the active agent interposedbetween the face surfaces. Alternatively, the active agent may becontained in a plurality of microcapsules distributed throughout thepermeable adhesive layer. In either case, the active agent is deliveredcontinuously from the reservoir or microcapsules through a membrane intothe active agent permeable adhesive, which is in contact with the skinor mucosa of the recipient. If the active agent is absorbed through theskin, a controlled and predetermined flow of the active agent isadministered to the recipient. In the case of microcapsules, theencapsulating agent may also function as the membrane.

In another device for transdermally administering the compounds inaccordance with the present invention, the pharmaceutically activecompound is contained in a matrix from which it is delivered in thedesired gradual, constant and controlled rate. The matrix is permeableto the release of the compound through diffusion or microporous flow.The release is rate controlling. Such a system, which requires nomembrane is described in U.S. Pat. No. 3,921,636. At least two types ofrelease are possible in these systems. Release by diffusion occurs whenthe matrix is non-porous. The phrmaceutically effective compounddissolves in and diffuses through the matrix itself. Release bymicroporous flow occurs when the pharmaceutically effective compound istransported through a liquid phase in the pores of the matrix.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure as come within known or customary practice within theart.

As used in this application:

a) the term "patient" refers to warm blooded animals such as, forexample, guinea pigs, mice, rats, cats, rabbits, dogs, monkeys,chimpanzees, and humans;

b) the term "treat" refers to the ability of the compounds to eitherrelieve, alleviate, or slow the progression of the patient's disease orprophylactically prevent its occurence or the manifestation of itssymptoms;

c) the term "neurodegeneration" refers to a progressive death anddisappearance of a population of nerve cells occurring in a mannercharacteristic of a particular disease state and leading to braindamage.

The compounds of Formula I may also be admixed with any inert carrierand utilized in laboratory assays in order to determine theconcentration of the compounds within the serum, urine, etc., of thepatient as is known in the art.

Neurodegenerative diseases are typically associated with a loss of NMDAreceptors. Thus, the compounds of Formulae Ia through Ic may be utilizedin diagnostic procedures to aid physicians with the diagnosis ofneurodegenerative diseases. The compounds may be labelled with imagingagents known in the art such as isotopic atoms and administered to apatient in order to determine whether the patient is exhibiting adecreased number of NMDA receptors and the rate at which that loss isoccurring.

What is claimed is:
 1. A compound of the formula: ##STR87## in which Zis represented by H, C₁ -C₄ alkyl, phenyl, substituted phenyl in whichthe phenyl ring may be optionally substituted with up to 3 substituents,wherein each substituent is independently selected from the groupconsisting of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CF₃, OCF₃, OH, CN, NH₂and NO₂, or a phenylalkyl substituent in which the phenyl ring may beoptionally substituted with up to 3 substituents, wherein eachsubstituent is independently selected from the group consisting ofhalogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CF₃, OCF₃, OH, CN, NH₂ and NO₂ ; R isrepresented by hydrogen, halogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, CF₃,OCF₃, OH, NO₂, or CN; B is represented by hydrogen, C₁ -C₄ alkyl,phenylalkyl substitutent in which the phenyl ring may be optionallysubstituted with up to 3 substituents, wherein each substituent isindependently selected from the group consisting of halogen, C₁₋₄ alkyl,C₁₋₄ alkoxy, CF₃, OCF3, OH, CN, NH₂ and NO₂, or --CH₂ --COR₂ ; X isrepresented by C(O); A is represented by: ##STR88## R₁, R₂, and D areeach independently represented by a substituent selected from the groupconsisting of --OH, --OR₃, --NR₄ R₅, --OCH₂ OR₃, and --O--(CH₂)_(m)--NR₆ R₇, in which m is an integer from 1-4; R₃ is represented by C₁ -C₄alkyl, phenyl, substituted phenyl in which the phenyl ring may beoptionally substituted with up to 3 substituents, wherein eachsubstituent is independently selected from the group consisting ofhalogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CF₃, OCF₃, OH, CN, NH₂ and NO₂, or aphenylalkyl substituent in which the phenyl ring may be optionallysubstituted with up to 3 substituents, wherein each substituent isindependently selected from the group consisting of haalogen, C₁₋₄alkyl, C₁₋₄ alkoxy, CF₃, OCF₃, OH, CN, NH₂ and NO₂ ; R₄ and R₅ are eachindependently represented by hydrogen or a C₁ -C₄ alkyl; R₆ and R₇ areeach independently represented by hydrogen or a C₁ -C₄ alkyl; and thepharmaceuticaly acceptable salts thereof, with the proviso that withrespect to a substituted phenyl ring, there may not be more than one NH2or NO2 nor both an alkoxy and a hydroxy on an one phenyl ring.
 2. Acompound according to claim 1 in which said compound is 3-(methyloxalylate)amino!-2-carbmethoxy-indole.
 3. A compound according toclaim 1 in which said compound is 3- (oxalyl)amino!-2-carboxy-indole. 4.A compound according to claim 1 in which said compound is 3-(methyloxalylate)amino!-2-carbethoxy-4,6-dichloroindole.
 5. A compoundaccording to claim 1 in which said compound is 3-(oxalyl)amino!-2-carboxy-4,6-dichloroindole.
 6. A compound according toclaim 1 in which said compound is 3-(methyloxalylate)benzylamino!-2-carbethoxy-4,6-dichloroindole.
 7. Acompound according to claim 1 in which said compound is 3-oxalyl)benzylamino!-2-carboxy-4,6-dichloroindole.
 8. A compoundaccording to claim 1 in which said compound is 3-(methyloxalylate)methylamino!-2-carbethoxy-4,6-dichloroindole.
 9. Acompound according to claim 1 in which said compound is 3-(oxalyl)methylamino!-2-carboxy-4,6-dichloroindole.